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Journal articles on the topic 'Mitochondrial alterations'
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Shen, Liang, and Xianquan Zhan. "Mitochondrial Dysfunction Pathway Alterations Offer Potential Biomarkers and Therapeutic Targets for Ovarian Cancer." Oxidative Medicine and Cellular Longevity 2022 (April 20, 2022): 1–22. http://dx.doi.org/10.1155/2022/5634724.
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The mitochondrion is a very versatile organelle that participates in some important cancer-associated biological processes, including energy metabolism, oxidative stress, mitochondrial DNA (mtDNA) mutation, cell apoptosis, mitochondria-nuclear communication, dynamics, autophagy, calcium overload, immunity, and drug resistance in ovarian cancer. Multiomics studies have found that mitochondrial dysfunction, oxidative stress, and apoptosis signaling pathways act in human ovarian cancer, which demonstrates that mitochondria play critical roles in ovarian cancer. Many molecular targeted drugs have been developed against mitochondrial dysfunction pathways in ovarian cancer, including olive leaf extract, nilotinib, salinomycin, Sambucus nigra agglutinin, tigecycline, and eupatilin. This review article focuses on the underlying biological roles of mitochondrial dysfunction in ovarian cancer progression based on omics data, potential molecular relationship between mitochondrial dysfunction and oxidative stress, and future perspectives of promising biomarkers and therapeutic targets based on the mitochondrial dysfunction pathway for ovarian cancer.
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Kim, Hyoung Kyu, Won Sun Park, Sung Hyun Kang, et al. "Mitochondrial alterations in human gastric carcinoma cell line." American Journal of Physiology-Cell Physiology 293, no. 2 (2007): C761—C771. http://dx.doi.org/10.1152/ajpcell.00043.2007.
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We compared mitochondrial function, morphology, and proteome in the rat normal gastric cell line RGM-1 and the human gastric cancer cell line AGS. Total numbers and cross-sectional sizes of mitochondria were smaller in AGS cells. Mitochondria in AGS cells were deformed and consumed less oxygen. Confocal microscopy indicated that the mitochondrial inner membrane potential was hyperpolarized and the mitochondrial Ca2+concentration was elevated in AGS cells. Interestingly, two-dimensional electrophoresis proteomics on the mitochondria-enriched fraction revealed high expression of four mitochondrial proteins in AGS cells: ubiquinol-cytochrome c reductase, mitochondrial short-chain enoyl-coenzyme A hydratase-1, heat shock protein 60, and mitochondria elongation factor Tu. The results provide clues as to the mechanism of the mitochondrial changes in cancer at the protein level and may serve as potential cancer biomarkers in mitochondria.
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Lenzi, Paola, Francesca Biagioni, Carla L. Busceti, et al. "Alterations of Mitochondrial Structure in Methamphetamine Toxicity." International Journal of Molecular Sciences 23, no. 16 (2022): 8926. http://dx.doi.org/10.3390/ijms23168926.
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Recent evidence shows that methamphetamine (METH) produces mitochondrial alterations that contribute to neurotoxicity. Nonetheless, most of these studies focus on mitochondrial activity, whereas mitochondrial morphology remains poorly investigated. In fact, morphological evidence about the fine structure of mitochondria during METH toxicity is not available. Thus, in the present study we analyzed dose-dependent mitochondrial structural alterations during METH exposure. Light and transmission electron microscopy were used, along with ultrastructural stoichiometry of catecholamine cells following various doses of METH. In the first part of the study cell death and cell degeneration were assessed and they were correlated with mitochondrial alterations observed using light microscopy. In the second part of the study, ultrastructural evidence of specific mitochondrial alterations of crests, inner and outer membranes and matrix were quantified, along with in situ alterations of mitochondrial proteins. Neurodegeneration induced by METH correlates significantly with specific mitochondrial damage, which allows definition of a scoring system for mitochondrial integrity. In turn, mitochondrial alterations are concomitant with a decrease in fission/mitophagy protein Fis1 and DRP1 and an increase in Pink1 and Parkin in situ, at the mitochondrial level. These findings provide structural evidence that mitochondria represent both direct and indirect targets of METH-induced toxicity
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Ludwig, Rebecca, Bimala Malla, Maria Höhrhan, Carmen Infante-Duarte, and Lina Anderhalten. "Investigating the Mitoprotective Effects of S1P Receptor Modulators Ex Vivo Using a Novel Semi-Automated Live Imaging Set-Up." International Journal of Molecular Sciences 25, no. 1 (2023): 261. http://dx.doi.org/10.3390/ijms25010261.
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In multiple sclerosis (MS), mitochondrial alterations appear to contribute to disease progression. The sphingosine-1-phosphate receptor modulator siponimod is approved for treating secondary progressive MS. Its preceding compound fingolimod was shown to prevent oxidative stress-induced alterations in mitochondrial morphology. Here, we assessed the effects of siponimod, compared to fingolimod, on neuronal mitochondria in oxidatively stressed hippocampal slices. We have also advanced the model of chronic organotypic hippocampal slices for live imaging, enabling semi-automated monitoring of mitochondrial alterations. The slices were prepared from B6.Cg-Tg(Thy1-CFP/COX8A)S2Lich/J mice that display fluorescent neuronal mitochondria. They were treated with hydrogen peroxide (oxidative stress paradigm) ± 1 nM siponimod or fingolimod for 24 h. Afterwards, mitochondrial dynamics were investigated. Under oxidative stress, the fraction of motile mitochondria decreased and mitochondria were shorter, smaller, and covered smaller distances. Siponimod partly prevented oxidatively induced alterations in mitochondrial morphology; for fingolimod, a similar trend was observed. Siponimod reduced the decrease in mitochondrial track displacement, while both compounds significantly increased track speed and preserved motility. The novel established imaging and analysis tools are suitable for assessing the dynamics of neuronal mitochondria ex vivo. Using these approaches, we showed that siponimod at 1 nM partially prevented oxidatively induced mitochondrial alterations in chronic brain slices.
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McCormick, A. Louise, Vanessa L. Smith, Dar Chow, and Edward S. Mocarski. "Disruption of Mitochondrial Networks by the Human Cytomegalovirus UL37 Gene Product Viral Mitochondrion-Localized Inhibitor of Apoptosis." Journal of Virology 77, no. 1 (2003): 631–41. http://dx.doi.org/10.1128/jvi.77.1.631-641.2003.
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ABSTRACT By 24 h after infection with human cytomegalovirus, the reticular mitochondrial network characteristic of uninfected fibroblasts was disrupted as mitochondria became punctate and dispersed. These alterations were associated with expression of the immediate-early (α) antiapoptotic UL37x1 gene product viral mitochondrion-localized inhibitor of apoptosis (vMIA). Similar alterations in mitochondrial morphology were induced directly by vMIA in transfected cells. A 68-amino-acid antiapoptotic derivative of vMIA containing the mitochondrial localization and antiapoptotic domains also induced disruption, whereas a mutant lacking the antiapoptotic domain failed to cause disruption. These data suggest that the fission and/or fusion process that normally controls mitochondrial networks is altered by vMIA. Mitochondrial fission has been implicated in the induction of apoptosis and vMIA-mediated inhibition of apoptosis may occur subsequent to this event.
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Kurt, Yasemin Gulcan, Bulent Kurt, Tuncer Cayci, and Emin Ozgur Akgul. "Mitochondrial DNA alterations in colorectal cancer cell lines." Journal of Nippon Medical School 79, no. 3 (2012): 244. http://dx.doi.org/10.1272/jnms.79.244.
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Gao, Kuo, Meiying Niu, Xing Zhai, Youliang Huang, Xin Tian, and Tiangang Li. "Genetic and non-genetic factors responsible for mitochondrial failure and Alzheimer’s disease." Genetika 46, no. 2 (2014): 631–47. http://dx.doi.org/10.2298/gensr1402631g.
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The objective of this review article is to explain the factors responsible for damaged mitochondria and its association with Alzheimer?s disease. Alzheimer?s disease (AD) is fairly produced by dysfunctional mitochondria that are alternatively caused by excessive reactive oxygen species and mitochondrial dynamic imbalance. In the pathogenesis of AD, there is important role of many factors including amyloid-beta peptide (A ), tau-proteins, and mutations in presenilin-1. Additionally, mitochondrial-targeted antioxidants have also been explained because of their significance to mitochondrial alterations in AD. Moreover, alteration in mitochondrial dynamics is responsible for the generation of segregated, damaged mitochondria that are, later on, destroyed through mitochondrial autophagy in AD. Finally, various novel models used for studying Alzheimer?s disease, have been discussed.
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Simcox, Eve M., Amy Reeve, and Doug Turnbull. "Monitoring mitochondrial dynamics and complex I dysfunction in neurons: implications for Parkinson's disease." Biochemical Society Transactions 41, no. 6 (2013): 1618–24. http://dx.doi.org/10.1042/bst20130189.
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Mitochondrial dynamics are essential for maintaining organelle stability and function. Through fission, fusion and mitophagic events, optimal populations of mitochondria are retained. Subsequently, alterations in such processes can have profound effects on the individual mitochondrion and the cell within which they reside. Neurons are post-mitotic energy-dependent cells and, as such, are particularly vulnerable to alterations in cellular bioenergetics and increased stress that may occur as a direct or indirect result of mitochondrial dysfunction. The trafficking of mitochondria to areas of higher energy requirements, such as synapses, where mitochondrial densities fluctuate, further highlights the importance of efficient mitochondrial dynamics in neurons. PD (Parkinson's disease) is a common progressive neurodegenerative disorder which is characterized by the loss of dopaminergic neurons within the substantia nigra. Complex I, the largest of all of the components of the electron transport chain is heavily implicated in PD pathogenesis. The exact series of events that lead to cell loss, however, are not fully elucidated, but are likely to involve dysfunction of mitochondria, their trafficking and dynamics.
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Gordon, J. A., and V. H. Gattone. "Mitochondrial alterations in cisplatin-induced acute renal failure." American Journal of Physiology-Renal Physiology 250, no. 6 (1986): F991—F998. http://dx.doi.org/10.1152/ajprenal.1986.250.6.f991.
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The mild reversible nonoliguric form of acute renal failure is perhaps the most common of many nephrotoxic side effects that occur secondary to cisplatin administration. The present studies were undertaken to gain insight into mitochondria alterations and morphological abnormalities underlying this form of renal failure. Following a single intraperitoneal injection of 5.5 mg/kg body wt of cisplatin changes in renal function, mitochondrial respiration, and calcium accumulation were measured serially over a 9-day period. Results indicate that reversible functional changes secondary to cisplatin are accompanied by changes in mitochondrial respiration and calcium accumulation. A decline in state 3 mitochondrial respiration precedes mitochondrial calcium accumulation. However, calcium accumulation begins to recover before mitochondrial respiration. At the peak of functional and biochemical injury morphological damage is extensive, and mitochondria are strikingly aberrant. The results demonstrate that changes in mitochondrial respiration and calcium accumulation occur secondary to cisplatin administration. Both of these effects may play a role in the renal cellular injury induced by cisplatin.
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Leão Barros, Mariceli Baia, Danilo do Rosário Pinheiro, and Bárbara do Nascimento Borges. "Mitochondrial DNA Alterations in Glioblastoma (GBM)." International Journal of Molecular Sciences 22, no. 11 (2021): 5855. http://dx.doi.org/10.3390/ijms22115855.
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Glioblastoma (GBM) is an extremely aggressive tumor originating from neural stem cells of the central nervous system, which has high histopathological and genomic diversity. Mitochondria are cellular organelles associated with the regulation of cellular metabolism, redox signaling, energy generation, regulation of cell proliferation, and apoptosis. Accumulation of mutations in mitochondrial DNA (mtDNA) leads to mitochondrial dysfunction that plays an important role in GBM pathogenesis, favoring abnormal energy and reactive oxygen species production and resistance to apoptosis and to chemotherapeutic agents. The present review summarizes the known mitochondrial DNA alterations related to GBM, their cellular and metabolic consequences, and their association with diagnosis, prognosis, and treatment.
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Malla, Bimala, Samuel Cotten, Rebecca Ulshoefer, et al. "Teriflunomide preserves peripheral nerve mitochondria from oxidative stress-mediated alterations." Therapeutic Advances in Chronic Disease 11 (January 2020): 204062232094477. http://dx.doi.org/10.1177/2040622320944773.
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Mitochondrial dysfunction is a common pathological hallmark in various inflammatory and degenerative diseases of the central nervous system, including multiple sclerosis (MS). We previously showed that oxidative stress alters axonal mitochondria, limiting their transport and inducing conformational changes that lead to axonal damage. Teriflunomide (TFN), an oral immunomodulatory drug approved for the treatment of relapsing forms of MS, reversibly inhibits dihydroorotate dehydrogenase (DHODH). DHODH is crucial for de novo pyrimidine biosynthesis and is the only mitochondrial enzyme in this pathway, thus conferring a link between inflammation, mitochondrial activity and axonal integrity. Here, we investigated how DHODH inhibition may affect mitochondrial behavior in the context of oxidative stress. We employed a model of transected murine spinal roots, previously developed in our laboratory. Using confocal live imaging of axonal mitochondria, we showed that in unmanipulated axons, TFN increased significantly the mitochondria length without altering their transport features. In mitochondria challenged with 50 µM hydrogen peroxide (H2O2) to induce oxidative stress, the presence of TFN at 1 µM concentration was able to restore mitochondrial shape, motility, as well as mitochondrial oxidation potential to control levels. No effects were observed at 5 µM TFN, while some shape and motility parameters were restored to control levels at 50 µM TFN. Thus, our data demonstrate an undescribed link between DHODH and mitochondrial dynamics and point to a potential neuroprotective effect of DHODH inhibition in the context of oxidative stress-induced damage of axonal mitochondria.
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Lee, Yun Haeng, Myeong Uk Kuk, Moon Kyoung So, et al. "Targeting Mitochondrial Oxidative Stress as a Strategy to Treat Aging and Age-Related Diseases." Antioxidants 12, no. 4 (2023): 934. http://dx.doi.org/10.3390/antiox12040934.
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Mitochondria are one of the organelles undergoing rapid alteration during the senescence process. Senescent cells show an increase in mitochondrial size, which is attributed to the accumulation of defective mitochondria, which causes mitochondrial oxidative stress. Defective mitochondria are also targets of mitochondrial oxidative stress, and the vicious cycle between defective mitochondria and mitochondrial oxidative stress contributes to the onset and development of aging and age-related diseases. Based on the findings, strategies to reduce mitochondrial oxidative stress have been suggested for the effective treatment of aging and age-related diseases. In this article, we discuss mitochondrial alterations and the consequent increase in mitochondrial oxidative stress. Then, the causal role of mitochondrial oxidative stress on aging is investigated by examining how aging and age-related diseases are exacerbated by induced stress. Furthermore, we assess the importance of targeting mitochondrial oxidative stress for the regulation of aging and suggest different therapeutic strategies to reduce mitochondrial oxidative stress. Therefore, this review will not only shed light on a new perspective on the role of mitochondrial oxidative stress in aging but also provide effective therapeutic strategies for the treatment of aging and age-related diseases through the regulation of mitochondrial oxidative stress.
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Portz, Philipp, та Michael K. Lee. "Changes in Drp1 Function and Mitochondrial Morphology Are Associated with the α-Synuclein Pathology in a Transgenic Mouse Model of Parkinson’s Disease". Cells 10, № 4 (2021): 885. http://dx.doi.org/10.3390/cells10040885.
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Alterations in mitochondrial function and morphology are associated with many human diseases, including cancer and neurodegenerative diseases. Mitochondrial impairment is linked to Parkinson’s disease (PD) pathogenesis, and alterations in mitochondrial dynamics are seen in PD models. In particular, α-synuclein (αS) abnormalities are often associated with pathological changes to mitochondria. However, the relationship between αS pathology and mitochondrial dynamics remains poorly defined. Herein, we examined a mouse model of α-synucleinopathy for αS pathology-linked alterations in mitochondrial dynamics in vivo. We show that α-synucleinopathy in a transgenic (Tg) mouse model expressing familial PD-linked mutant A53T human αS (TgA53T) is associated with a decrease in Drp1 localization and activity in the mitochondria. In addition, we show that the loss of Drp1 function in the mitochondria is associated with two distinct phenotypes of enlarged neuronal mitochondria. Mitochondrial enlargement was only present in diseased animals and, apart from Drp1, other proteins involved in mitochondrial dynamics are unlikely to cause these changes, as their levels remained mostly unchanged. Further, the levels of Mfn1, a protein that facilitates mitochondrial fusion, was decreased nonspecifically with transgene expression. These results support the view that altered mitochondrial dynamics are a significant neuropathological factor in α-synucleinopathies.
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Dragoni, Francesca, Jessica Garau, Daisy Sproviero, et al. "Characterization of Mitochondrial Alterations in Aicardi–Goutières Patients Mutated in RNASEH2A and RNASEH2B Genes." International Journal of Molecular Sciences 23, no. 22 (2022): 14482. http://dx.doi.org/10.3390/ijms232214482.
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Aicardi–Goutières syndrome (AGS) is a rare encephalopathy characterized by neurological and immunological features. Mitochondrial dysfunctions may lead to mitochondrial DNA (mtDNA) release and consequent immune system activation. We investigated the role of mitochondria and mtDNA in AGS pathogenesis by studying patients mutated in RNASEH2B and RNASEH2A genes. Lymphoblastoid cell lines (LCLs) from RNASEH2A- and RNASEH2B-mutated patients and healthy control were used. Transmission Electron Microscopy (TEM) and flow cytometry were used to assess morphological alterations, reactive oxygen species (ROS) production and mitochondrial membrane potential variations. Seahorse Analyzer was used to investigate metabolic alterations, and mtDNA oxidation and VDAC1 oligomerization were assessed by immunofluorescence. Western blot and RT-qPCR were used to quantify mtTFA protein and mtDNA release. Morphological alterations of mitochondria were observed in both mutated LCLs, and loss of physiological membrane potential was mainly identified in RNASEH2A LCLs. ROS production and 8-oxoGuanine levels were increased in RNASEH2B LCLs. Additionally, the VDAC1 signal was increased, suggesting a mitochondrial pore formation possibly determining mtDNA release. Indeed, higher cytoplasmic mtDNA levels were found in RNASEH2B LCLs. Metabolic alterations confirmed mitochondrial damage in both LCLs. Data highlighted mitochondrial alterations in AGS patients’ LCLs suggesting a pivotal role in AGS pathogenesis.
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Gómez-Serrano, María, Emilio Camafeita, Marta Loureiro, and Belén Peral. "Mitoproteomics: Tackling Mitochondrial Dysfunction in Human Disease." Oxidative Medicine and Cellular Longevity 2018 (November 8, 2018): 1–26. http://dx.doi.org/10.1155/2018/1435934.
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Mitochondria are highly dynamic and regulated organelles that historically have been defined based on their crucial role in cell metabolism. However, they are implicated in a variety of other important functions, making mitochondrial dysfunction an important axis in several pathological contexts. Despite that conventional biochemical and molecular biology approaches have provided significant insight into mitochondrial functionality, innovative techniques that provide a global view of the mitochondrion are still necessary. Proteomics fulfils this need by enabling accurate, systems-wide quantitative analysis of protein abundance. More importantly, redox proteomics approaches offer unique opportunities to tackle oxidative stress, a phenomenon that is intimately linked to aging, cardiovascular disease, and cancer. In addition, cutting-edge proteomics approaches reveal how proteins exert their functions in complex interaction networks where even subtle alterations stemming from early pathological states can be monitored. Here, we describe the proteomics approaches that will help to deepen the role of mitochondria in health and disease by assessing not only changes to mitochondrial protein composition but also alterations to their redox state and how protein interaction networks regulate mitochondrial function and dynamics. This review is aimed at showing the reader how the application of proteomics approaches during the last 20 years has revealed crucial mitochondrial roles in the context of aging, neurodegenerative disorders, metabolic disease, and cancer.
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Barrera, M. J., I. Castro, P. Carvajal, et al. "POS0455 TOFACITINIB DECREASES INFLAMMATORY MARKERS AND MITOCHONDRIAL MORPHOLOGICAL DAMAGE IN SALIVARY GLANDS OF A MURINE MODEL OF SJÖGREN’S SYNDROME." Annals of the Rheumatic Diseases 81, Suppl 1 (2022): 481.2–482. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2110.
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BackgroundAltered homeostasis of salivary gland (SG) epithelial cells in Sjögren’s syndrome (SS) patients could be the initiating factor that leads to inflammation, as well as secretory dysfunction. Mitochondria are important organelles involved in cellular metabolism and their dysfunction can induce a loss of homeostasis and inflammation. Altered mitochondrion can release mitochondrial components that can act as damage-associated molecular patterns (DAMPs) and induce an inflammatory response via pattern recognition receptors (PRRs) such as the NLRP3 inflammasome, TLR9, cGAS/STING, and ZBP1 (1). Previously we determined that SG from SS patients showed and altered autophagy, which is associated to an increased pro-inflammatory cytokines expression. Interestingly, increased expression of pro-inflammatory markers such as IL-6, was reversed by JAK inhibitor tofacitinib in three-dimensional (3D)-acini deficient in autophagy (2). It is not clear whether the alterations in autophagy found in SG patients include alterations in mitochondrial clearance (mitophagy) that may lead to the accumulation of damaged mitochondria and enhanced inflammation. In this context, recent results of our laboratory showed, for the first time, severe ultrastructural alterations of mitochondria in SG cells from SS patients (1). However, it remains to be determined if these alterations are related to inflammation and if an anti-inflammatory agent could regulate these processes.ObjectivesTo analyze the effect of tofacitinib on the mitochondrial ultrastructure in submandibular glands of a murine model of SS. In addition, to evaluate the effect of tofacitinib on the expression and activation of some PRRs involved in the recognition of mitochondrial DAMPs in the same murine model.MethodsSix-month-old female NOD.B10Sn-H2b/J mice (Jackson Laboratories, USA) were used with 4-5 mice per group. Procedures were approved by the Universidad de Chile Animal Care and Use Committee. 30 mg/kg/day tofacitinib citrate was administered by oral gavage. After 28 days of tofacitinib or vehicle administration, their submandibular glands were obtained, which were processed to evaluate the mitochondrial ultrastructure by electron microscopy or lysed in RIPA buffer to obtain proteins. The protein levels of PRRs: NLRP3, TLR9, ZBP-1, and cGAs, as well as molecules activated downstream of cGAS and ZBP-1 such as TBK1, pTBK1, pSTING, and STING were determined by Western blotting.ResultsThe results show that the mitochondria of the glandular epithelial cells of NOD.B10Sn-H2b/J mice treated with vehicle (control) present alterations such as swelling, disruption of membranes and crest disorganization that previously were reported in patients with SS (1). Interestingly, tofacitinib treatment improves the architecture of mitochondria. On the other hand, the protein levels of PRRs such as NLRP3 and cGAS decreased in mice treated with tofacitinib, as well as pTBK1.ConclusionThe altered morphology of mitochondria together with the increased protein levels of PRRs and downstream markers of these PRRs suggests release of mitochondrial DAMPs in submandibular glands of NOD.B10Sn-H2b/J mice. The improvement in mitochondrial morphology as well as the decrease in PRRs activation under tofacitinib treatment suggest a potential use of this anti-inflammatory agent in mitochondrial alterations associated with inflammation. Many questions remain to be addressed, such as determining which mitochondrial DAMP might be being released and whether this is associated with impaired mitochondrial function in SS.References[1]Barrera, M. J., et al (2021). Dysfunctional mitochondria as critical players in the inflammation of autoimmune diseases: Potential role in Sjögren’s syndrome. Autoimmunity reviews, 20(8), 102867.[2]Barrera, M. J., et al (2021). Tofacitinib counteracts IL-6 overexpression induced by deficient autophagy: implications in Sjögren’s syndrome. Rheumatology (Oxford, England), 60(4), 1951–1962.AcknowledgementsThis work was supported by Fondecyt Iniciación 11201058 and Fondecyt-Chile 1210055.Disclosure of InterestsNone declared.
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Marques, Ana P., Rosa Resende, Diana F. Silva, et al. "Mitochondrial Alterations in Fibroblasts of Early Stage Bipolar Disorder Patients." Biomedicines 9, no. 5 (2021): 522. http://dx.doi.org/10.3390/biomedicines9050522.
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This study aims to evaluate whether mitochondrial changes occur in the early stages of bipolar disorder (BD). Using fibroblasts derived from BD patients and matched controls, the levels of proteins involved in mitochondrial biogenesis and dynamics (fission and fusion) were evaluated by Western Blot analysis. Mitochondrial membrane potential (MMP) was studied using the fluorescent probe TMRE. Mitochondrial morphology was analyzed with the probe Mitotracker Green and mitophagy was evaluated by quantifying the co-localization of HSP60 (mitochondria marker) and LC3B (autophagosome marker) by immunofluorescence. Furthermore, the activity of the mitochondrial respiratory chain and the glycolytic capacity of controls and BD patients-derived cells were also studied using the Seahorse technology. BD patient-derived fibroblasts exhibit fragmented mitochondria concomitantly with changes in mitochondrial dynamics and biogenesis in comparison with controls. Moreover, a decrease in the MMP and increased mitophagy was observed in fibroblasts obtained from BD patients when compared with control cells. Impaired energetic metabolism due to inhibition of the mitochondrial electron transport chain (ETC) and subsequent ATP depletion, associated with glycolysis stimulation, was also a feature of BD fibroblasts. Overall, these results support the fact that mitochondrial disturbance is an early event implicated in BD pathophysiology that might trigger neuronal changes and modification of brain circuitry.
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Van Itallie, C. M., S. Van Why, G. Thulin, M. Kashgarian, and N. J. Siegel. "Alterations in mitochondrial RNA expression after renal ischemia." American Journal of Physiology-Cell Physiology 265, no. 3 (1993): C712—C719. http://dx.doi.org/10.1152/ajpcell.1993.265.3.c712.
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Ischemia and reperfusion damage mitochondrial structure and impair respiratory function. In this study, 45 min of renal ischemia followed by varying periods of reflow profoundly depressed the activity of several respiratory complexes in mitochondria isolated from rat kidneys. The respiratory complexes are composed of subunits encoded by both the nuclear and mitochondrial genomes. To determine the role of mitochondrial gene expression in recovery of respiratory function, expression of mitochondrial RNA was examined during reperfusion. Both mature and incompletely processed cytochrome b mRNA levels were depressed after 45 min of ischemia and 15 min of reflow; levels rebounded to above normal after 2 h of reflow and then declined over the next 22 h. Another mitochondrial RNA showed a similar pattern; in contrast, the levels of a nuclear-encoded subunit mRNA for a respiratory enzyme and of 28S rRNA were unchanged. These data demonstrate that renal ischemia followed by reperfusion alters mitochondrial RNA expression. We speculate that mitochondrial RNA turnover is increased in response to continuing injury and that recovery is accompanied by enhanced RNA synthesis.
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Hatch, Grant M. "Cell biology of cardiac mitochondrial phospholipids." Biochemistry and Cell Biology 82, no. 1 (2004): 99–112. http://dx.doi.org/10.1139/o03-074.
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Phospholipids are important structural and functional components of all biological membranes and define the compartmentation of organelles. Mitochondrial phospholipids comprise a significant proportion of the entire phospholipid content of most eukaroytic cells. In the heart, a tissue rich in mitochondria, the mitochondrial phospholipids provide for diverse roles in the regulation of various mitochondrial processes including apoptosis, electron transport, and mitochondrial lipid and protein import. It is well documented that alteration in the content and fatty acid composition of phospholipids within the heart is linked to alterations in myocardial electrical activity. In addition, reduction in the specific mitochondrial phospholipid cardiolipin is an underlying biochemical cause of Barth Syndrome, a rare and often fatal X-linked genetic disease that is associated with cardiomyopathy. Thus, maintenance of both the content and molecular composition of phospholipids synthesized within the mitochondria is essential for normal cardiac function. This review will focus on the function and regulation of the biosynthesis and resynthesis of mitochondrial phospholipids in the mammalian heart.Key words: phospholipid, metabolism, heart, cardiolipin, mitochondria.
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Lenzi, Paola, Rosangela Ferese, Francesca Biagioni, et al. "Rapamycin Ameliorates Defects in Mitochondrial Fission and Mitophagy in Glioblastoma Cells." International Journal of Molecular Sciences 22, no. 10 (2021): 5379. http://dx.doi.org/10.3390/ijms22105379.
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Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of the present study consists of detailing an mTOR-dependent mitophagy occlusion, along with suppression of mitochondrial fission. These phenomena contribute to explain the increase in altered mitochondria reported here. Administration of the mTOR inhibitor rapamycin rescues mitochondrial alterations. In detail, rapamycin induces the expression of genes promoting mitophagy (PINK1, PARKIN, ULK1, AMBRA1) and mitochondrial fission (FIS1, DRP1). This occurs along with over-expression of VPS34, an early gene placed upstream in the autophagy pathway. The topographic stoichiometry of proteins coded by these genes within mitochondria indicates that, a remarkable polarization of proteins involved in fission and mitophagy within mitochondria including LC3 takes place. Co-localization of these proteins within mitochondria, persists for weeks following rapamycin, which produces long-lasting mitochondrial plasticity. Thus, rapamycin restores mitochondrial status in GBM cells. These findings add novel evidence about mitochondria and GBM, while fostering a novel therapeutic approach to restore healthy mitochondria through mTOR inhibition.
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Lee, Yun Haeng, Ji Yun Park, Haneur Lee, et al. "Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence." Cells 10, no. 11 (2021): 3003. http://dx.doi.org/10.3390/cells10113003.
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Mitochondria are one of organelles that undergo significant changes associated with senescence. An increase in mitochondrial size is observed in senescent cells, and this increase is ascribed to the accumulation of dysfunctional mitochondria that generate excessive reactive oxygen species (ROS). Such dysfunctional mitochondria are prime targets for ROS-induced damage, which leads to the deterioration of oxidative phosphorylation and increased dependence on glycolysis as an energy source. Based on findings indicating that senescent cells exhibit mitochondrial metabolic alterations, a strategy to induce mitochondrial metabolic reprogramming has been proposed to treat aging and age-related diseases. In this review, we discuss senescence-related mitochondrial changes and consequent mitochondrial metabolic alterations. We assess the significance of mitochondrial metabolic reprogramming for senescence regulation and propose the appropriate control of mitochondrial metabolism to ameliorate senescence. Learning how to regulate mitochondrial metabolism will provide knowledge for the control of aging and age-related pathologies. Further research focusing on mitochondrial metabolic reprogramming will be an important guide for the development of anti-aging therapies, and will provide novel strategies for anti-aging interventions.
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Rickard, Brittany P., Marta Overchuk, Vesna A. Chappell, et al. "Methods to Evaluate Changes in Mitochondrial Structure and Function in Cancer." Cancers 15, no. 9 (2023): 2564. http://dx.doi.org/10.3390/cancers15092564.
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Mitochondria are regulators of key cellular processes, including energy production and redox homeostasis. Mitochondrial dysfunction is associated with various human diseases, including cancer. Importantly, both structural and functional changes can alter mitochondrial function. Morphologic and quantifiable changes in mitochondria can affect their function and contribute to disease. Structural mitochondrial changes include alterations in cristae morphology, mitochondrial DNA integrity and quantity, and dynamics, such as fission and fusion. Functional parameters related to mitochondrial biology include the production of reactive oxygen species, bioenergetic capacity, calcium retention, and membrane potential. Although these parameters can occur independently of one another, changes in mitochondrial structure and function are often interrelated. Thus, evaluating changes in both mitochondrial structure and function is crucial to understanding the molecular events involved in disease onset and progression. This review focuses on the relationship between alterations in mitochondrial structure and function and cancer, with a particular emphasis on gynecologic malignancies. Selecting methods with tractable parameters may be critical to identifying and targeting mitochondria-related therapeutic options. Methods to measure changes in mitochondrial structure and function, with the associated benefits and limitations, are summarized.
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Zheng, Yunsi, Anqi Luo, and Xiaoquan Liu. "The Imbalance of Mitochondrial Fusion/Fission Drives High-Glucose-Induced Vascular Injury." Biomolecules 11, no. 12 (2021): 1779. http://dx.doi.org/10.3390/biom11121779.
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Emerging evidence shows that mitochondria fusion/fission imbalance is related to the occurrence of hyperglycemia-induced vascular injury. To study the temporal dynamics of mitochondrial fusion and fission, we observed the alteration of mitochondrial fusion/fission proteins in a set of different high-glucose exposure durations, especially in the early stage of hyperglycemia. The in vitro results show that persistent cellular apoptosis and endothelial dysfunction can be induced rapidly within 12 hours’ high-glucose pre-incubation. Our results show that mitochondria maintain normal morphology and function within 4 hours’ high-glucose pre-incubation; with the extended high-glucose exposure, there is a transition to progressive fragmentation; once severe mitochondria fusion/fission imbalance occurs, persistent cellular apoptosis will develop. In vitro and in vivo results consistently suggest that mitochondrial fusion/fission homeostasis alterations trigger high-glucose-induced vascular injury. As the guardian of mitochondria, AMPK is suppressed in response to hyperglycemia, resulting in imbalanced mitochondrial fusion/fission, which can be reversed by AMPK stimulation. Our results suggest that mitochondrial fusion/fission’s staged homeostasis may be a predictive factor of diabetic cardiovascular complications.
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Chacko, Balu, Colin Reily, Gloria A. Benavides, Balaraman Kalyanaraman, Michael P. Murphy, and Victor Darley-Usmar. "Alterations in Mitochondrial Bioenergetics by Mitochondrially-Targeted Compounds." Free Radical Biology and Medicine 51 (November 2011): S84. http://dx.doi.org/10.1016/j.freeradbiomed.2011.10.392.
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Rosca, Mariana G., Vincent M. Monnier, Luke I. Szweda, and Miriam F. Weiss. "Alterations in renal mitochondrial respiration in response to the reactive oxoaldehyde methylglyoxal." American Journal of Physiology-Renal Physiology 283, no. 1 (2002): F52—F59. http://dx.doi.org/10.1152/ajprenal.00302.2001.
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Chronic hyperglycemia has been linked to alterations in mitochondrial function, suggesting an important role in the pathophysiology of the complications of diabetes mellitus. In the diabetic kidney, ultrastructural changes in mitochondria are associated with impaired tubular function. The goal of this study was to determine if methylglyoxal (MGO), a dicarbonyl compound reaching high levels in hyperglycemic conditions, has direct toxicity for renal mitochondria. Intact mitochondria isolated from the renal cortex of rats were incubated with MGO to determine 1) its effect on mitochondrial respiration, 2) the conditions under which MGO exerts these effects, and 3) the potential mitochondrial targets of MGO influence. This study demonstrates that MGO has an inhibitory effect on both the tricarboxylic acid cycle and the electron respiratory chain. The modifications appear to be specific to certain mitochondrial proteins. Alterations of these proteins lead to disturbances in mitochondria that may play an important role in renal cellular toxicity and in the development of diabetic nephropathy.
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Spuch, Carlos, Saida Ortolano, and Carmen Navarro. "New Insights in the Amyloid-Beta Interaction with Mitochondria." Journal of Aging Research 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/324968.
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Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD). Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP) has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both proteins are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species production, cause mitochondrial damage, and prevent neurons from functioning normally. In this paper, we will outline current knowledge of the intracellular localization of amyloid-beta. Moreover, we summarize evidence from AD postmortem brain as well as animal AD models showing that amyloid-beta triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. Thus, this paper supports the Alzheimer cascade mitochondrial hypothesis such as the most important early events in this disease, and probably one of the future strategies on the therapy of this neurodegenerative disease.
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Musicco, Clara, Anna Signorile, Vito Pesce, Paola Loguercio Polosa, and Antonella Cormio. "Mitochondria Deregulations in Cancer Offer Several Potential Targets of Therapeutic Interventions." International Journal of Molecular Sciences 24, no. 13 (2023): 10420. http://dx.doi.org/10.3390/ijms241310420.
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Mitochondria play a key role in cancer and their involvement is not limited to the production of ATP only. Mitochondria also produce reactive oxygen species and building blocks to sustain rapid cell proliferation; thus, the deregulation of mitochondrial function is associated with cancer disease development and progression. In cancer cells, a metabolic reprogramming takes place through a different modulation of the mitochondrial metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, the Krebs cycle, glutamine and heme metabolism. Alterations of mitochondrial homeostasis, in particular, of mitochondrial biogenesis, mitophagy, dynamics, redox balance, and protein homeostasis, were also observed in cancer cells. The use of drugs acting on mitochondrial destabilization may represent a promising therapeutic approach in tumors in which mitochondrial respiration is the predominant energy source. In this review, we summarize the main mitochondrial features and metabolic pathways altered in cancer cells, moreover, we present the best known drugs that, by acting on mitochondrial homeostasis and metabolic pathways, may induce mitochondrial alterations and cancer cell death. In addition, new strategies that induce mitochondrial damage, such as photodynamic, photothermal and chemodynamic therapies, and the development of nanoformulations that specifically target drugs in mitochondria are also described. Thus, mitochondria-targeted drugs may open new frontiers to a tailored and personalized cancer therapy.
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Lee, Wei-Hua, Vijesh J. Bhute, Hitoshi Higuchi, Sakae Ikeda, Sean P. Palecek, and Akihiro Ikeda. "Metabolic alterations caused by the mutation and overexpression of the Tmem135 gene." Experimental Biology and Medicine 245, no. 17 (2020): 1571–83. http://dx.doi.org/10.1177/1535370220932856.
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Mitochondria are dynamic organelles that undergo fission and fusion. While they are essential for cellular metabolism, the effect of dysregulated mitochondrial dynamics on cellular metabolism is not fully understood. We previously found that transmembrane protein 135 ( Tmem135) plays a role in the regulation of mitochondrial dynamics in mice. Mice homozygous for a Tmem135 mutation ( Tmem135FUN025/FUN025) display accelerated aging and age-related disease pathologies in the retina including the retinal pigment epithelium (RPE). We also generated a transgenic mouse line globally overexpressing the Tmem135 gene ( Tmem135 TG). In several tissues and cells that we studied such as the retina, heart, and fibroblast cells, we observed that the Tmem135 mutation causes elongated mitochondria, while overexpression of Tmem135 results in fragmented mitochondria. To investigate how abnormal mitochondrial dynamics affect metabolic signatures of tissues and cells, we identified metabolic changes in primary RPE cell cultures as well as heart, cerebellum, and hippocampus isolated from Tmem135FUN025/FUN025 mice (fusion > fission) and Tmem135 TG mice (fusion < fission) using nuclear magnetic resonance spectroscopy. Metabolomics analysis revealed a tissue-dependent response to Tmem135 alterations, whereby significant metabolic changes were observed in the heart of both Tmem135 mutant and TG mice as compared to wild-type, while negligible effects were observed in the cerebellum and hippocampus. We also observed changes in Tmem135FUN025/FUN025 and Tmem135 TG RPE cells associated with osmosis and glucose and phospholipid metabolism. We observed depletion of NAD+ in both Tmem135FUN025/FUN025 and Tmem135 TG RPE cells, indicating that imbalance in mitochondrial dynamics to both directions lowers the cellular NAD+ level. Metabolic changes identified in this study might be associated with imbalanced mitochondrial dynamics in heart tissue and RPE cells which can likely lead to functional abnormalities. Impact statement Mitochondria are dynamic organelles undergoing fission and fusion. Proper regulation of this process is important for healthy aging process, as aberrant mitochondrial dynamics are associated with several age-related diseases/pathologies. However, it is not well understood how imbalanced mitochondrial dynamics may lead to those diseases and pathologies. Here, we aimed to determine metabolic alterations in tissues and cells from mouse models with over-fused (fusion > fission) and over-fragmented (fusion < fission) mitochondria that display age-related disease pathologies. Our results indicated tissue-dependent sensitivity to these mitochondrial changes, and metabolic pathways likely affected by aberrant mitochondrial dynamics. This study provides new insights into how dysregulated mitochondrial dynamics could lead to functional abnormalities of tissues and cells.
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Friedlander, Joseph E., Ning Shen, Aozhuo Zeng, Sovannarith Korm, and Hui Feng. "Failure to Guard: Mitochondrial Protein Quality Control in Cancer." International Journal of Molecular Sciences 22, no. 15 (2021): 8306. http://dx.doi.org/10.3390/ijms22158306.
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Mitochondria are energetic and dynamic organelles with a crucial role in bioenergetics, metabolism, and signaling. Mitochondrial proteins, encoded by both nuclear and mitochondrial DNA, must be properly regulated to ensure proteostasis. Mitochondrial protein quality control (MPQC) serves as a critical surveillance system, employing different pathways and regulators as cellular guardians to ensure mitochondrial protein quality and quantity. In this review, we describe key pathways and players in MPQC, such as mitochondrial protein translocation-associated degradation, mitochondrial stress responses, chaperones, and proteases, and how they work together to safeguard mitochondrial health and integrity. Deregulated MPQC leads to proteotoxicity and dysfunctional mitochondria, which contributes to numerous human diseases, including cancer. We discuss how alterations in MPQC components are linked to tumorigenesis, whether they act as drivers, suppressors, or both. Finally, we summarize recent advances that seek to target these alterations for the development of anti-cancer drugs.
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Guerra, Flora, Giulia Girolimetti, Raffaella Beli, et al. "Synergistic Effect of Mitochondrial and Lysosomal Dysfunction in Parkinson’s Disease." Cells 8, no. 5 (2019): 452. http://dx.doi.org/10.3390/cells8050452.
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Crosstalk between lysosomes and mitochondria plays a central role in Parkinson’s Disease (PD). Lysosomal function may be influenced by mitochondrial quality control, dynamics and/or respiration, but whether dysfunction of endocytic or autophagic pathway is associated with mitochondrial impairment determining accumulation of defective mitochondria, is not yet understood. Here, we performed live imaging, western blotting analysis, sequencing of mitochondrial DNA (mtDNA) and senescence-associated beta-galactosidase activity assay on primary fibroblasts from a young patient affected by PD, her mother and a healthy control to analyze the occurrence of mtDNA mutations, lysosomal abundance, acidification and function, mitochondrial biogenesis activation and senescence. We showed synergistic alterations in lysosomal functions and mitochondrial biogenesis, likely associated with a mitochondrial genetic defect, with a consequent block of mitochondrial turnover and occurrence of premature cellular senescence in PARK2-PD fibroblasts, suggesting that these alterations represent potential mechanisms contributing to the loss of dopaminergic neurons.
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Muñoz, Juan Pablo, Fernanda Luisa Basei, María Laura Rojas, David Galvis, and Antonio Zorzano. "Mechanisms of Modulation of Mitochondrial Architecture." Biomolecules 13, no. 8 (2023): 1225. http://dx.doi.org/10.3390/biom13081225.
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Mitochondrial network architecture plays a critical role in cellular physiology. Indeed, alterations in the shape of mitochondria upon exposure to cellular stress can cause the dysfunction of these organelles. In this scenario, mitochondrial dynamics proteins and the phospholipid composition of the mitochondrial membrane are key for fine-tuning the modulation of mitochondrial architecture. In addition, several factors including post-translational modifications such as the phosphorylation, acetylation, SUMOylation, and o-GlcNAcylation of mitochondrial dynamics proteins contribute to shaping the plasticity of this architecture. In this regard, several studies have evidenced that, upon metabolic stress, mitochondrial dynamics proteins are post-translationally modified, leading to the alteration of mitochondrial architecture. Interestingly, several proteins that sustain the mitochondrial lipid composition also modulate mitochondrial morphology and organelle communication. In this context, pharmacological studies have revealed that the modulation of mitochondrial shape and function emerges as a potential therapeutic strategy for metabolic diseases. Here, we review the factors that modulate mitochondrial architecture.
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Ramachandran, Anup, David S. Umbaugh, and Hartmut Jaeschke. "Mitochondrial Dynamics in Drug-Induced Liver Injury." Livers 1, no. 3 (2021): 102–15. http://dx.doi.org/10.3390/livers1030010.
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Mitochondria have been studied for decades from the standpoint of metabolism and ATP generation. However, in recent years mitochondrial dynamics and its influence on bioenergetics and cellular homeostasis is also being appreciated. Mitochondria undergo regular cycles of fusion and fission regulated by various cues including cellular energy requirements and pathophysiological stimuli, and the network of critical proteins and membrane lipids involved in mitochondrial dynamics is being revealed. Hepatocytes are highly metabolic cells which have abundant mitochondria suggesting a biologically relevant role for mitochondrial dynamics in hepatocyte injury and recovery. Here we review information on molecular mediators of mitochondrial dynamics and their alteration in drug-induced liver injury. Based on current information, it is evident that changes in mitochondrial fusion and fission are hallmarks of liver pathophysiology ranging from acetaminophen-induced or cholestatic liver injury to chronic liver diseases. These alterations in mitochondrial dynamics influence multiple related mitochondrial responses such as mitophagy and mitochondrial biogenesis, which are important adaptive responses facilitating liver recovery in several contexts, including drug-induced liver injury. The current focus on characterization of molecular mechanisms of mitochondrial dynamics is of immense relevance to liver pathophysiology and have the potential to provide significant insight into mechanisms of liver recovery and regeneration after injury.
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Garcia Saez, Ana J. "Mitochondrial alterations in apoptosis." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1863 (September 2022): 148791. http://dx.doi.org/10.1016/j.bbabio.2022.148791.
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Cosentino, Katia, and Ana J. García-Sáez. "Mitochondrial alterations in apoptosis." Chemistry and Physics of Lipids 181 (July 2014): 62–75. http://dx.doi.org/10.1016/j.chemphyslip.2014.04.001.
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Baloyannis, Stavros J., Vassiliki Costa, and Demetrios Michmizos. "Mitochondrial alterations Alzheimer's disease." American Journal of Alzheimer's Disease & Other Dementiasr 19, no. 2 (2004): 89–93. http://dx.doi.org/10.1177/153331750401900205.
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Umbaugh, David S., Nga T. Nguyen, Hartmut Jaeschke, and Anup Ramachandran. "Mitochondrial Membrane Potential Drives Early Change in Mitochondrial Morphology After Acetaminophen Exposure." Toxicological Sciences 180, no. 1 (2021): 186–95. http://dx.doi.org/10.1093/toxsci/kfaa188.
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Abstract Mitochondrial morphology plays a critical role in regulating mitochondrial and cellular function. It is well established that oxidative stress and mitochondrial injury are central to acetaminophen (APAP) hepatotoxicity. However, the role of mitochondrial dynamics, namely the remodeling of mitochondrial morphology through fusion and fission, has largely gone unexplored. To investigate this, we used primary mouse hepatocytes treated with APAP which allowed for real-time visualization of mitochondrial morphology using mitotracker green. We found that alterations in mitochondrial morphology were dose dependent, with a biphasic response in mitochondrial shape at higher APAP doses. Importantly, these two distinct mitochondrial morphologies corresponded with differences in mitochondrial respiratory function and polarization. The early change in mitochondrial morphology can be reversible and appears to be an adaptive response caused by alterations in membrane potential, which ultimately help preserve mitochondrial function. The later delayed change in mitochondrial morphology is irreversible and is driven by loss of mitochondrial membrane potential, decreased canonical fusion proteins, and alterations in mitochondrial lipid composition. Collectively, these later changes tilt the scales toward mitochondrial fission resulting in fragmented mitochondria with reduced functionality. This work provides evidence of adaptive early changes in mitochondrial morphology, which results in functional consequences that are dictated by the severity of APAP overdose.
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Pinheiro, DO, MD Silva, and EA Gregório. "Mitochondria in the midgut epithelial cells of sugarcane borer parasitized by Cotesia flavipes (Cameron, 1891)." Brazilian Journal of Biology 70, no. 1 (2010): 163–69. http://dx.doi.org/10.1590/s1519-69842010000100023.
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The sugarcane borer Diatraea saccharalis (Lepidoptera: Crambidae) has been controlled by Cotesia flavipes (Hymenoptera: Braconidae); however, very little is known about the effect of the parasitism in the host organs, including the midgut. This work aims to verify mitochondrial alteration in the different midgut epithelial cells of D. saccharalis parasitized by C. flavipes. Midgut fragments (anterior and posterior region) of both non-parasitized and parasitized larvae were processed for transmission electron microscopy. The mitochondria of midgut epithelial cell in the parasitized larvae exhibit morphological alteration, represented by matrix rarefaction and vacuolisation. These mitochondrial alterations are more pronounced in the anterior midgut region during the parasitism process, mainly in the columnar cell.
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Baloyannis, Stavros J. "Mitochondria Are Related to Synaptic Pathology in Alzheimer's Disease." International Journal of Alzheimer's Disease 2011 (2011): 1–7. http://dx.doi.org/10.4061/2011/305395.
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Morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer's disease, been associated with oxidative stress and Aβ-peptide-induced toxicity. We proceeded to estimation of mitochondria on electron micrographs of autopsy specimens of Alzheimer's disease. We found substantial morphological and morphometric changes of the mitochondria in the neurons of the hippocampus, the neocortex, the cerebellar cortex, the thalamus, the globus pallidus, the red nucleus, the locus coeruleus, and the climbing fibers. The alterations consisted of considerable changes of the cristae, accumulation of osmiophilic material, and modification of the shape and size. Mitochondrial alterations were prominent in neurons, which showed a depletion of dendritic spines and loss of dendritic branches. Mitochondrial alterations are not related with the accumulation of amyloid deposits, but are prominent whenever fragmentation of the Golgi apparatus exists. Morphometric analysis showed also that mitochondria are significantly reduced in neurons, which demonstrated synaptic pathology.
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Saleem, Ayesha, Sobia Iqbal, Yuan Zhang, and David A. Hood. "Effect of p53 on mitochondrial morphology, import, and assembly in skeletal muscle." American Journal of Physiology-Cell Physiology 308, no. 4 (2015): C319—C329. http://dx.doi.org/10.1152/ajpcell.00253.2014.
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The purpose of this study was to investigate whether p53 regulates mitochondrial function via changes in mitochondrial protein import, complex IV (COX) assembly, or the expression of key proteins involved in mitochondrial dynamics and degradation. Mitochondria from p53 KO mice displayed ultra-structural alterations and were more punctate in appearance. This was accompanied by protein-specific alterations in fission, fusion, and mitophagy-related proteins. However, matrix-destined protein import into subsarcolemmal or intermyofibrillar mitochondria was unaffected in the absence of p53, despite mitochondrial subfraction-specific reductions in Tom20, Tim23, mtHsp70, and mtHsp60 in the knockout (KO) mitochondria. Complex IV activity in isolated mitochondria was also unchanged in KO mice, but two-dimensional blue native-PAGE revealed a reduction in the assembly of complex IV within the IMF fractions from KO mice in tandem with lower levels of the assembly protein Surf1. This observed defect in complex IV assembly may facilitate the previously documented impairment in mitochondrial function in p53 KO mice. We suspect that these morphological and functional impairments in mitochondria drive a decreased reliance on mitochondrial respiration as a means of energy production in skeletal muscle in the absence of p53.
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Lucas, David T., Prafulla Aryal, Luke I. Szweda, Walter J. Koch, and Leslie A. Leinwand. "Alterations in mitochondrial function in a mouse model of hypertrophic cardiomyopathy." American Journal of Physiology-Heart and Circulatory Physiology 284, no. 2 (2003): H575—H583. http://dx.doi.org/10.1152/ajpheart.00619.2002.
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Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by varying degrees of ventricular hypertrophy and myofibrillar disarray. Mutations in cardiac contractile proteins cause HCM. However, there is an unexplained wide variability in the clinical phenotype, and it is likely that there are multiple contributing factors. Because mitochondrial dysfunction has been described in heart disease, we tested the hypothesis that mitochondrial dysfunction contributes to the varying HCM phenotypes. Mitochondrial function was assessed in two transgenic models of HCM: mice with a mutant myosin heavy chain gene (MyHC) or with a mutant cardiac troponin T (R92Q) gene. Despite mitochondrial ultrastructural abnormalities in both models, the rate of state 3 respiration was significantly decreased only in the mutant MyHC mice by ∼23%. Notably, this decrease in state 3 respiration preceded hemodynamic dysfunction. The maximum activity of α-ketogutarate dehydrogenase as assayed in isolated disrupted mitochondria was decreased by 28% compared with isolated control mitochondria. In addition, complexes I and IV were decreased in mutant MyHC transgenic mice. Inhibition of β-adrenergic receptor kinase, which is elevated in mutant MyHC mouse hearts, can prevent mitochondrial respiratory impairment in mutant MyHC mice. Thus our results suggest that mitochondria may contribute to the hemodynamic dysfunction seen in some forms of HCM and offer a plausible mechanism responsible for some of the heterogeneity of the disease phenotypes.
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Roy, Kim, and Sankaramoorthy. "Mitochondrial Structural Changes in the Pathogenesis of Diabetic Retinopathy." Journal of Clinical Medicine 8, no. 9 (2019): 1363. http://dx.doi.org/10.3390/jcm8091363.
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Abstract: At the core of proper mitochondrial functionality is the maintenance of its structure and morphology. Physical changes in mitochondrial structure alter metabolic pathways inside mitochondria, affect mitochondrial turnover, disturb mitochondrial dynamics, and promote mitochondrial fragmentation, ultimately triggering apoptosis. In high glucose condition, increased mitochondrial fragmentation contributes to apoptotic death in retinal vascular and Müller cells. Although alterations in mitochondrial morphology have been detected in several diabetic tissues, it remains to be established in the vascular cells of the diabetic retina. From a mechanistic standpoint, our current work supports the notion that increased expression of fission genes and decreased expression of fusion genes are involved in promoting excessive mitochondrial fragmentation. While mechanistic insights are only beginning to reveal how high glucose alters mitochondrial morphology, the consequences are clearly seen as release of cytochrome c from fragmented mitochondria triggers apoptosis. Current findings raise the prospect of targeting excessive mitochondrial fragmentation as a potential therapeutic strategy for treatment of diabetic retinopathy. While biochemical and epigenetic changes have been reported to be associated with mitochondrial dysfunction, this review focuses on alterations in mitochondrial morphology, and their impact on mitochondrial function and pathogenesis of diabetic retinopathy.
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Vanišová, M., D. Burská, J. Křížová, et al. "Stable COX17 Downregulation Leads to Alterations in Mitochondrial Ultrastructure, Decreased Copper Content and Impaired Cytochrome c Oxidase Biogenesis in HEK293 Cells." Folia Biologica 65, no. 4 (2019): 181–87. http://dx.doi.org/10.14712/fb2019065040181.
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Cox17 is an assembly factor that participates in early cytochrome c oxidase (COX, CcO) assembly stages. Cox17 shuttles copper ions from the cytosol to the mitochondria and, together with Sco1 and Sco2, provides copper ions to the Cox1 and Cox2 mitochondrially encoded subunits. In Saccharomyces cerevisiae, Cox17 also modulates mitochondrial membrane architecture due to the interaction of Cox17 with proteins of the MICOS complex (mitochondrial contact site and cristae organizing system). There is currently no data regarding the impact of long-term Cox17 deficiency in human cells. Here, we present construction and characterization of three stable COX17 shRNA-downregulated HEK293 cell lines that have less than 10 % of the residual Cox17 protein level. Cox17-depleted cell lines exhibited decreased intramitochondrial copper content, decreased CcO subunit levels (Cox1, Cox4 and Cox5a) and accumulation of CcO subcomplexes. Similarly to yeast cells, mitochondria in Cox17-downregulated HEK293 cell lines exhibited ultrastructural changes including cristae reduction and mitochondrial swelling. Characterization of the molecular pathogenesis of long-term Cox17 deficiency complements our knowledge of the mitochondrial copper metabolism and assembly of cytochrome c oxidase in human cells.
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Vongsfak, Jirapong, Wasana Pratchayasakul, Nattayaporn Apaijai, Tanat Vaniyapong, Nipon Chattipakorn, and Siriporn C. Chattipakorn. "The Alterations in Mitochondrial Dynamics Following Cerebral Ischemia/Reperfusion Injury." Antioxidants 10, no. 9 (2021): 1384. http://dx.doi.org/10.3390/antiox10091384.
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Cerebral ischemia results in a poor oxygen supply and cerebral infarction. Reperfusion to the ischemic area is the best therapeutic approach. Although reperfusion after ischemia has beneficial effects, it also causes ischemia/reperfusion (I/R) injury. Increases in oxidative stress, mitochondrial dysfunction, and cell death in the brain, resulting in brain infarction, have also been observed following cerebral I/R injury. Mitochondria are dynamic organelles, including mitochondrial fusion and fission. Both processes are essential for mitochondrial homeostasis and cell survival. Several studies demonstrated that an imbalance in mitochondrial dynamics after cerebral ischemia, with or without reperfusion injury, plays an important role in the regulation of cell survival and infarct area size. Mitochondrial dysmorphology/dysfunction and inflammatory processes also occur after cerebral ischemia. Knowledge surrounding the mechanisms involved in the imbalance in mitochondrial dynamics following cerebral ischemia with or without reperfusion injury would help in the prevention or treatment of the adverse effects of cerebral injury. Therefore, this review aims to summarize and discuss the roles of mitochondrial dynamics, mitochondrial function, and inflammatory processes in cerebral ischemia with or without reperfusion injury from in vitro and in vivo studies. Any contradictory findings are incorporated and discussed.
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Malla, Bimala, Agustin Liotta, Helena Bros, et al. "Teriflunomide Preserves Neuronal Activity and Protects Mitochondria in Brain Slices Exposed to Oxidative Stress." International Journal of Molecular Sciences 23, no. 3 (2022): 1538. http://dx.doi.org/10.3390/ijms23031538.
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Teriflunomide (TFN) limits relapses in relapsing–remitting multiple sclerosis (RRMS) by reducing lymphocytic proliferation through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and the subsequent modulation of de novo pyrimidine synthesis. Alterations of mitochondrial function as a consequence of oxidative stress have been reported during neuroinflammation. Previously, we showed that TFN prevents alterations of mitochondrial motility caused by oxidative stress in peripheral axons. Here, we aimed to validate TFN effects on mitochondria and neuronal activity in hippocampal brain slices, in which cellular distribution and synaptic circuits are largely preserved. TFN effects on metabolism and neuronal activity were investigated by assessing oxygen partial pressure and local field potential in acute slices. Additionally, we imaged mitochondria in brain slices from the transgenic Thy1-CFP/COX8A)S2Lich/J (mitoCFP) mice using two-photon microscopy. Although TFN could not prevent oxidative stress-related depletion of ATP, it preserved oxygen consumption and neuronal activity in CNS tissue during oxidative stress. Furthermore, TFN prevented mitochondrial shortening and fragmentation of puncta-shaped and network mitochondria during oxidative stress. Regarding motility, TFN accentuated the decrease in mitochondrial displacement and increase in speed observed during oxidative stress. Importantly, these effects were not associated with neuronal viability and did not lead to axonal damage. In conclusion, during conditions of oxidative stress, TFN preserves the functionality of neurons and prevents morphological and motility alterations of mitochondria.
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Warnsmann, Verena, Jana Meisterknecht, Ilka Wittig, and Heinz D. Osiewacz. "Aging of Podospora anserina Leads to Alterations of OXPHOS and the Induction of Non-Mitochondrial Salvage Pathways." Cells 10, no. 12 (2021): 3319. http://dx.doi.org/10.3390/cells10123319.
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The accumulation of functionally impaired mitochondria is a key event in aging. Previous works with the fungal aging model Podospora anserina demonstrated pronounced age-dependent changes of mitochondrial morphology and ultrastructure, as well as alterations of transcript and protein levels, including individual proteins of the oxidative phosphorylation (OXPHOS). The identified protein changes do not reflect the level of the whole protein complexes as they function in-vivo. In the present study, we investigated in detail the age-dependent changes of assembled mitochondrial protein complexes, using complexome profiling. We observed pronounced age-depen-dent alterations of the OXPHOS complexes, including the loss of mitochondrial respiratory supercomplexes (mtRSCs) and a reduction in the abundance of complex I and complex IV. Additionally, we identified a switch from the standard complex IV-dependent respiration to an alternative respiration during the aging of the P. anserina wild type. Interestingly, we identified proteasome components, as well as endoplasmic reticulum (ER) proteins, for which the recruitment to mitochondria appeared to be increased in the mitochondria of older cultures. Overall, our data demonstrate pronounced age-dependent alterations of the protein complexes involved in energy transduction and suggest the induction of different non-mitochondrial salvage pathways, to counteract the age-dependent mitochondrial impairments which occur during aging.
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Avagliano, Angelica, Maria Rosaria Ruocco, Federica Aliotta, et al. "Mitochondrial Flexibility of Breast Cancers: A Growth Advantage and a Therapeutic Opportunity." Cells 8, no. 5 (2019): 401. http://dx.doi.org/10.3390/cells8050401.
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Breast cancers are very heterogeneous tissues with several cell types and metabolic pathways together sustaining the initiation and progression of disease and contributing to evasion from cancer therapies. Furthermore, breast cancer cells have an impressive metabolic plasticity that is regulated by the heterogeneous tumour microenvironment through bidirectional interactions. The structure and accessibility of nutrients within this unstable microenvironment influence the metabolism of cancer cells that shift between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to produce adenosine triphosphate (ATP). In this scenario, the mitochondrial energetic pathways of cancer cells can be reprogrammed to modulate breast cancer’s progression and aggressiveness. Moreover, mitochondrial alterations can lead to crosstalk between the mitochondria and the nucleus, and subsequently affect cancer tissue properties. This article reviewed the metabolic plasticity of breast cancer cells, focussing mainly on breast cancer mitochondrial metabolic reprogramming and the mitochondrial alterations influencing nuclear pathways. Finally, the therapeutic strategies targeting molecules and pathways regulating cancer mitochondrial alterations are highlighted.
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Wasmus, Christina, and Jan Dudek. "Metabolic Alterations Caused by Defective Cardiolipin Remodeling in Inherited Cardiomyopathies." Life 10, no. 11 (2020): 277. http://dx.doi.org/10.3390/life10110277.
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The heart is the most energy-consuming organ in the human body. In heart failure, the homeostasis of energy supply and demand is endangered by an increase in cardiomyocyte workload, or by an insufficiency in energy-providing processes. Energy metabolism is directly associated with mitochondrial redox homeostasis. The production of toxic reactive oxygen species (ROS) may overwhelm mitochondrial and cellular ROS defense mechanisms in case of heart failure. Mitochondria are essential cell organelles and provide 95% of the required energy in the heart. Metabolic remodeling, changes in mitochondrial structure or function, and alterations in mitochondrial calcium signaling diminish mitochondrial energy provision in many forms of cardiomyopathy. The mitochondrial respiratory chain creates a proton gradient across the inner mitochondrial membrane, which couples respiration with oxidative phosphorylation and the preservation of energy in the chemical bonds of ATP. Akin to other mitochondrial enzymes, the respiratory chain is integrated into the inner mitochondrial membrane. The tight association with the mitochondrial phospholipid cardiolipin (CL) ensures its structural integrity and coordinates enzymatic activity. This review focuses on how changes in mitochondrial CL may be associated with heart failure. Dysfunctional CL has been found in diabetic cardiomyopathy, ischemia reperfusion injury and the aging heart. Barth syndrome (BTHS) is caused by an inherited defect in the biosynthesis of cardiolipin. Moreover, a dysfunctional CL pool causes other types of rare inherited cardiomyopathies, such as Sengers syndrome and Dilated Cardiomyopathy with Ataxia (DCMA). Here we review the impact of cardiolipin deficiency on mitochondrial functions in cellular and animal models. We describe the molecular mechanisms concerning mitochondrial dysfunction as an incitement of cardiomyopathy and discuss potential therapeutic strategies.
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Bonora, Massimo, Sonia Missiroli, Mariasole Perrone, Francesco Fiorica, Paolo Pinton, and Carlotta Giorgi. "Mitochondrial Control of Genomic Instability in Cancer." Cancers 13, no. 8 (2021): 1914. http://dx.doi.org/10.3390/cancers13081914.
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Mitochondria are well known to participate in multiple aspects of tumor formation and progression. They indeed can alter the susceptibility of cells to engage regulated cell death, regulate pro-survival signal transduction pathways and confer metabolic plasticity that adapts to specific tumor cell demands. Interestingly, a relatively poorly explored aspect of mitochondria in neoplastic disease is their contribution to the characteristic genomic instability that underlies the evolution of the disease. In this review, we summarize the known mechanisms by which mitochondrial alterations in cancer tolerate and support the accumulation of DNA mutations which leads to genomic instability. We describe recent studies elucidating mitochondrial responses to DNA damage as well as the direct contribution of mitochondria to favor the accumulation of DNA alterations.
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Salgado, Josefa, Beatriz Honorato, and Jesús García-Foncillas. "Review: Mitochondrial Defects in Breast Cancer." Clinical medicine. Oncology 2 (January 2008): CMO.S524. http://dx.doi.org/10.4137/cmo.s524.
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Mitochondria play important roles in cellular energy metabolism, free radical generation, and apoptosis. Mitochondrial DNA has been proposed to be involved in carcinogenesis because of its high susceptibility to mutations and limited repair mechanisms in comparison to nuclear DNA. Breast cancer is the most frequent cancer type among women in the world and, although exhaustive research has been done on nuclear DNA changes, several studies describe a variety of mitochondrial DNA alterations present in breast cancer. In this review article, we to provide a summary of the mitochondrial genomic alterations reported in breast cancer and their functional consequences.
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Schatten, Heide, and Marian Lewis. "The Efects of Spaceflight on Mitochondria in Human Lymphocytes (Jurkat)." Microscopy and Microanalysis 5, S2 (1999): 1118–19. http://dx.doi.org/10.1017/s1431927600018912.
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Spaceflight induced mitochondrial alterations have been reported for muscle and may be associated with altered physiological functions in space. Mitochondrial alterations are also indicative of preapoptotic events which are seen in greater amounts in cells exposed to spaceflight when compared with cells cultured at 1 g. Preapoptotic mitochondrial changes include alterations of processes at the inner mitochondrial membrane and can result in changes in mitochondrial volume. Higher amounts of oxidative stress during space flight may be one of the causes for changes which lead to apoptosis. Jurkat cells flown on the STS-76 space shuttle mission showed an increase in the number of cells with apoptotic bodies early in the mission and a time-dependent, microgravity-related increase in the Fas/APO-1 cell death factor. Here we investigated the morphology of mitochondria in Jurkat cells exposed to spaceflight during the STS-76 mission.