bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2020‒10‒04
seventeen papers selected by
Avinash N. Mukkala
University of Toronto


  1. Redox Biol. 2020 Sep 19. pii: S2213-2317(20)30938-1. [Epub ahead of print]37 101733
    Milliken AS, Kulkarni CA, Brookes PS.
      Generation of mitochondrial reactive oxygen species (ROS) is an important process in triggering cellular necrosis and tissue infarction during ischemia-reperfusion (IR) injury. Ischemia results in accumulation of the metabolite succinate. Rapid oxidation of this succinate by mitochondrial complex II (Cx-II) during reperfusion reduces the co-enzyme Q (Co-Q) pool, thereby driving electrons backward into complex-I (Cx-I), a process known as reverse electron transport (RET), which is thought to be a major source of ROS. During ischemia, enhanced glycolysis results in an acidic cellular pH at the onset of reperfusion. While the process of RsET within Cx-I is known to be enhanced by a high mitochondrial trans-membrane ΔpH, the impact of pH itself on the integrated process of Cx-II to Cx-I RET has not been fully studied. Using isolated mouse heart and liver mitochondria under conditions which mimic the onset of reperfusion (i.e., high [ADP]), we show that mitochondrial respiration (state 2 and state 3) as well as isolated Cx-II activity are impaired at acidic pH, whereas the overall generation of ROS by Cx-II to Cx-I RET was insensitive to pH. Together these data indicate that the acceleration of Cx-I RET ROS by ΔpH appears to be cancelled out by the impact of pH on the source of electrons, i.e. Cx-II. Implications for the role of Cx-II to Cx-I RET derived ROS in IR injury are discussed.
    Keywords:  Acidosis; Complex I; Ischemia; Metabolism; Mitochondria; ROS
    DOI:  https://doi.org/10.1016/j.redox.2020.101733
  2. Front Cell Dev Biol. 2020 ;8 853
    Xin T, Lv W, Liu D, Jing Y, Hu F.
      Mitochondrial dysfunction contributes to cardiovascular disorders, especially post-infarction cardiac injury, through incompletely characterized mechanisms. Among the latter, increasing evidence points to alterations in mitochondrial quality control, a range of adaptive responses regulating mitochondrial morphology and function. Optic atrophy 1 (Opa1) is a mitochondrial inner membrane GTPase known to promote mitochondrial fusion. In this study, hypoxia-mediated cardiomyocyte damage was induced to mimic post-infarction cardiac injury in vitro. Loss- and gain-of-function assays were then performed to evaluate the impact of Opa1 expression on mitochondrial quality control and cardiomyocyte survival and function. Hypoxic stress reduced cardiomyocyte viability, impaired contractile/relaxation functions, and augmented the synthesis of pro-inflammatory mediators. These effects were exacerbated by Opa1 knockdown, and significantly attenuated by Opa1 overexpression. Mitochondrial quality control was disturbed by hypoxia, as reflected by multiple mitochondrial deficits; i.e., increased fission, defective fusion, impaired mitophagy, decreased biogenesis, increased oxidative stress, and blunted respiration. By contrast, overexpression of Opa1 normalized mitochondrial quality control and sustained cardiomyocyte function. We also found that ERK, AMPK, and YAP signaling can regulate Opa1 expression. These results identify Opa1 as a novel regulator of mitochondrial quality control and highlight a key role for Opa1 in protecting cardiomyocytes against post-infarction cardiac injury.
    Keywords:  Opa1; hypoxia; mitochondria; mitochondrial quality control; post-infarction cardiac injury
    DOI:  https://doi.org/10.3389/fcell.2020.00853
  3. Front Pharmacol. 2020 ;11 578599
    Gatti P, Ilamathi HS, Todkar K, Germain M.
      SARS-CoV-2 is a positive sense RNA coronavirus that constitutes a new threat for the global community and economy. While vaccines against SARS-CoV-2 are being developed, the mechanisms through which this virus takes control of an infected cell to replicate remains poorly understood. Upon infection, viruses completely rely on host cell molecular machinery to survive and replicate. To escape from the immune response and proliferate, viruses strategically modulate cellular metabolism and alter subcellular organelle architecture and functions. One way they do this is by modulating the structure and function of mitochondria, a critical cellular metabolic hub but also a key platform for the regulation of cellular immunity. This versatile nature of mitochondria defends host cells from viruses through several mechanisms including cellular apoptosis, ROS signaling, MAVS activation and mitochondrial DNA-dependent immune activation. These events are regulated by mitochondrial dynamics, a process by which mitochondria alter their structure (including their length and connectivity) in response to stress or other cues. It is therefore not surprising that viruses, including coronaviruses hijack these processes for their survival. In this review, we highlight how positive sense RNA viruses modulate mitochondrial dynamics and metabolism to evade mitochondrial mediated immune response in order to proliferate.
    Keywords:  RNA viruses; SARS-CoV-2; immune response; metabolism; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fphar.2020.578599
  4. Materials (Basel). 2020 Sep 29. pii: E4336. [Epub ahead of print]13(19):
    Jung M, Choi H, Kim J, Mun JY.
      Propionic acid is a metabolite of the microbiome and can be transported to the brain. Previous data show that propionic acid changes mitochondrial biogenesis in SH-SY5Y cells and induces abnormal autophagy in primary hippocampal neurons. Maintaining mitochondrial function is key to homeostasis in neuronal cells, and mitophagy is the selective autophagy involved in regulating mitochondrial quality. Monitoring mitophagy though light microscopy or conventional transmission electron microscopy separately is insufficient because phases of mitophagy, including autophagosome and autolysosome in nano-resolution, are critical for studies of function. Therefore, we used correlative light and electron microscopy to investigate mitochondrial quality in SH-SY5Y cells after propionic acid treatment to use the advantages of both techniques. We showed, with this approach, that propionic acid induces mitophagy associated with mitochondrial quality.
    Keywords:  autophagy; correlative light and electron microscopy (CLEM); mitophagy; propionic acid
    DOI:  https://doi.org/10.3390/ma13194336
  5. EMBO J. 2020 Oct 01. 39(19): e103530
    Beretta M, Santos CX, Molenaar C, Hafstad AD, Miller CC, Revazian A, Betteridge K, Schröder K, Streckfuß-Bömeke K, Doroshow JH, Fleck RA, Su TP, Belousov VV, Parsons M, Shah AM.
      Cells subjected to environmental stresses undergo regulated cell death (RCD) when homeostatic programs fail to maintain viability. A major mechanism of RCD is the excessive calcium loading of mitochondria and consequent triggering of the mitochondrial permeability transition (mPT), which is especially important in post-mitotic cells such as cardiomyocytes and neurons. Here, we show that stress-induced upregulation of the ROS-generating protein Nox4 at the ER-mitochondria contact sites (MAMs) is a pro-survival mechanism that inhibits calcium transfer through InsP3 receptors (InsP3 R). Nox4 mediates redox signaling at the MAM of stressed cells to augment Akt-dependent phosphorylation of InsP3 R, thereby inhibiting calcium flux and mPT-dependent necrosis. In hearts subjected to ischemia-reperfusion, Nox4 limits infarct size through this mechanism. These results uncover a hitherto unrecognized stress pathway, whereby a ROS-generating protein mediates pro-survival effects through spatially confined signaling at the MAM to regulate ER to mitochondria calcium flux and triggering of the mPT.
    Keywords:  InsP3 receptor; NADPH oxidase-4; calcium signaling; cell death; mitochondria-associated membrane
    DOI:  https://doi.org/10.15252/embj.2019103530
  6. Clin Transl Med. 2020 Sep;10(5): e166
    Lu L, Ma J, Tang J, Liu Y, Zheng Q, Chen S, Gao E, Ren J, Yang L, Yang J.
      BACKGROUND: Myocardial ischemia/reperfusion (MI/R) injury imposes devastating cardiovascular sequelae in particular cardiac dysfunction as a result of restored blood flow. However, the mechanism behind MI/R injury remains elusive. Mitochondrial ubiquitin ligase (MITOL/MARCH5) is localized at the mitochondria-ER contact site and may be activated in response to a variety of pathophysiological processes, such as apoptosis, mitochondrial injury, ER stress, hypoxia, and reactive oxygen species (ROS) generation. Irisin as a cleaved product of fibronectin type III domain-containing protein 5 (FNDC5) displays cardioprotection in diverse cardiac diseases.METHODS: This study was designed to examine the role of irisin and MITOL in MI/R injury. Male C57BL/6J mice (8-10-week-old) were administered adenovirus MITOL shRNA through intracardiac injection followed by MI/R surgery through ligation and release the slipknot of cardiac left anterior descending coronary artery.
    RESULTS: Our results showed that irisin improved myocardial function in the face of MI/R injury as evidenced by reduced myocardial infarct size, apoptotic rate, serum lactate dehydrogenase (LDH), ROS generation, and malondialdehyde (MDA) levels as well as lessened ER stress injury. Moreover, our results indicated that protective role of irisin was mediated by upregulation of MITOL. Irisin also protected H9c2 cells against simulated I/R through negating ER stress, apoptosis, ROS and MDA levels, as well as facilitating superoxide dismutase (SOD) by way of elevated MITOL expression.
    CONCLUSIONS: To this end, our data favored that irisin pretreatment protects against MI/R injury, ER stress, ROS production, and mitochondrial homeostasis through upregulation of MITOL. These findings depicted the therapeutic potential of irisin and MITOL in the management of MI/R injury in patients with ST-segment elevation.
    Keywords:  apoptosis; endoplasmic reticulum stress; irisin (FNDC5); mitochondrial ubiquitin ligase (MITOL); myocardial ischemia/reperfusion (MI/R); reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1002/ctm2.166
  7. Front Physiol. 2020 ;11 1054
    Alam S, Abdullah CS, Aishwarya R, Morshed M, Bhuiyan MS.
      Mitochondria are the key to properly functioning energy generation in the metabolically demanding cardiomyocytes and thus essential to healthy heart contractility on a beat-to-beat basis. Mitochondria being the central organelle for cellular metabolism and signaling in the heart, its dysfunction leads to cardiovascular disease. The healthy mitochondrial functioning critical to maintaining cardiomyocyte viability and contractility is accomplished by adaptive changes in the dynamics, biogenesis, and degradation of the mitochondria to ensure cellular proteostasis. Recent compelling evidence suggests that the classical protein quality control system in cardiomyocytes is also under constant mitochondrial control, either directly or indirectly. Impairment of cytosolic protein quality control may affect the position of the mitochondria in relation to other organelles, as well as mitochondrial morphology and function, and could also activate mitochondrial proteostasis. Despite a growing interest in the mitochondrial quality control system, very little information is available about the molecular function of mitochondria in cardiac proteostasis. In this review, we bring together current understanding of the adaptations and role of the mitochondria in cardiac proteostasis and describe the adaptive/maladaptive changes observed in the mitochondrial network required to maintain proteomic integrity. We also highlight the key mitochondrial signaling pathways activated in response to proteotoxic stress as a cellular mechanism to protect the heart from proteotoxicity. A deeper understanding of the molecular mechanisms of mitochondrial adaptations and their role in cardiac proteostasis will help to develop future therapeutics to protect the heart from cardiovascular diseases.
    Keywords:  cardiac proteostasis; mitochondria; mitochondrial dysfunction; mitochondrial proteostasis; mitochondrial unfolded protein response; proteotoxicity
    DOI:  https://doi.org/10.3389/fphys.2020.01054
  8. Int J Mol Sci. 2020 Sep 29. pii: E7202. [Epub ahead of print]21(19):
    Youn CK, Jun Y, Jo ER, Cho SI.
      Aging is associated with functional and morphological changes in the sensory organs, including the auditory system. Mitophagy, a process that regulates the turnover of dysfunctional mitochondria, is impaired with aging. This study aimed to investigate the effect of aging on mitophagy in the central auditory system using an age-related hearing loss mouse model. C57BL/6J mice were divided into the following four groups based on age: 1-, 6-, 12-, and 18-month groups. The hearing ability was evaluated by measuring the auditory brainstem response (ABR) thresholds. The mitochondrial DNA damage level and the expression of mitophagy-related genes, and proteins were investigated by real-time polymerase chain reaction and Western blot analyses. The colocalization of mitophagosomes and lysosomes in the mouse auditory cortex and inferior colliculus was analyzed by immunofluorescence analysis. The expression of genes involved in mitophagy, such as PINK1, Parkin, and BNIP3 in the mouse auditory cortex and inferior colliculus, was investigated by immunohistochemical staining. The ABR threshold increased with aging. In addition to the mitochondrial DNA integrity, the mRNA levels of PINK1, Parkin, NIX, and BNIP3, as well as the protein levels of PINK1, Parkin, BNIP3, COX4, LC3B, mitochondrial oxidative phosphorylation (OXPHOS) subunits I-IV in the mouse auditory cortex significantly decreased with aging. The immunofluorescence analysis revealed that the colocalization of mitophagosomes and lysosomes in the mouse auditory cortex and inferior colliculus decreased with aging. The immunohistochemical analysis revealed that the expression of PINK1, Parkin, and BNIP3 decreased in the mouse auditory cortex and inferior colliculus with aging. These findings indicate that aging-associated impaired mitophagy may contribute to the cellular changes observed in an aged central auditory system, which result in age-related hearing loss. Thus, the induction of mitophagy can be a potential therapeutic strategy for age-related hearing loss.
    Keywords:  age-related hearing loss; auditory cortex; mitochondria; mitophagy; presbycusis
    DOI:  https://doi.org/10.3390/ijms21197202
  9. Mol Biol Cell. 2020 Sep 30. mbcE20080524
    Friedl J, Knopp MR, Groh C, Paz E, Gould SB, Herrmann JM, Boos F.
      Most mitochondrial proteins are synthesized as precursors that carry N-terminal presequences. After import into mitochondria, these targeting signals are cleaved off by the mitochondrial processing peptidase MPP. Using the mitochondrial tandem protein Arg5,6 as model substrate, we demonstrate that MPP has an additional role in preprotein maturation, beyond the removal of presequences. Arg5,6 is synthesized as a polyprotein precursor that is imported into mitochondria and subsequently separated into two distinct enzymes. This internal processing is performed by MPP, which cleaves the Arg5,6 precursor at its N-terminus and at an internal site. The peculiar organization of Arg5,6 is conserved across fungi and reflects the polycistronic arginine operon in prokaryotes. MPP cleavage sites are also present in other mitochondrial fusion proteins from fungi, plants and animals. Hence, besides its role as "ticket canceller" for removal of presequences, MPP exhibits a second, conserved activity as internal processing peptidase for complex mitochondrial precursor proteins.
    DOI:  https://doi.org/10.1091/mbc.E20-08-0524
  10. Nat Cell Biol. 2020 Oct;22(10): 1180-1186
    Rey T, Zaganelli S, Cuillery E, Vartholomaiou E, Croisier M, Martinou JC, Manley S.
      Mitochondria contain the genetic information and expression machinery to produce essential respiratory chain proteins. Within the mitochondrial matrix, newly synthesized RNA, RNA processing proteins and mitoribosome assembly factors form punctate sub-compartments referred to as mitochondrial RNA granules (MRGs)1-3. Despite their proposed importance in regulating gene expression, the structural and dynamic properties of MRGs remain largely unknown. We investigated the internal architecture of MRGs using fluorescence super-resolution localization microscopy and correlative electron microscopy, and found that the MRG ultrastructure consists of compacted RNA embedded within a protein cloud. Using live-cell super-resolution structured illumination microscopy and fluorescence recovery after photobleaching, we reveal that MRGs rapidly exchange components and can undergo fusion, characteristic properties of fluid condensates4. Furthermore, MRGs associate with the inner mitochondrial membrane and their fusion coincides with mitochondrial remodelling. Inhibition of mitochondrial fission or fusion leads to an aberrant accumulation of MRGs into concentrated pockets, where they remain as distinct individual units despite their close apposition. Together, our findings reveal that MRGs are nanoscale fluid compartments, which are dispersed along mitochondria via membrane dynamics.
    DOI:  https://doi.org/10.1038/s41556-020-00584-8
  11. Int J Mol Sci. 2020 Sep 29. pii: E7185. [Epub ahead of print]21(19):
    Decuypere JP, Hutchinson S, Monbaliu D, Martinet W, Pirenne J, Jochmans I.
      Renal ischemia-reperfusion (IR) injury leading to cell death is a major cause of acute kidney injury, contributing to morbidity and mortality. Autophagy counteracts cell death by removing damaged macromolecules and organelles, making it an interesting anchor point for treatment strategies. However, autophagy is also suggested to enhance cell death when the ischemic burden is too strong. To investigate whether the role of autophagy depends on the severity of ischemic stress, we analyzed the dynamics of autophagy and apoptosis in an IR rat model with mild (45 min) or severe (60 min) renal ischemia. Following mild IR, renal injury was associated with reduced autophagy, enhanced mammalian target of rapamycin (mTOR) activity, and apoptosis. Severe IR, on the other hand, was associated with a higher autophagic activity, independent of mTOR, and without affecting apoptosis. Autophagy stimulation by trehalose injected 24 and 48 h prior to onset of severe ischemia did not reduce renal injury markers nor function, but reduced apoptosis and restored tubular dilation 7 days post reperfusion. This suggests that trehalose-dependent autophagy stimulation enhances tissue repair following an IR injury. Our data show that autophagy dynamics are strongly dependent on the severity of IR and that trehalose shows the potential to trigger autophagy-dependent repair processes following renal IR injury.
    Keywords:  acute kidney injury; apoptosis; autophagy; ischemia-reperfusion injury; trehalose
    DOI:  https://doi.org/10.3390/ijms21197185
  12. Mitochondrion. 2020 Sep 24. pii: S1567-7249(20)30194-X. [Epub ahead of print]
    Wang X, Weidling I, Koppel S, Menta B, Perez Ortiz J, Kalani A, Wilkins HM, Swerdlow RH.
      We screened cell line and plasma-derived exosomes for molecules that localize to mitochondria or that reflect mitochondrial integrity. SH-SY5Y cell-derived exosomes contained humanin, citrate synthase, and fibroblast growth factor 21 protein, and plasma-derived exosomes contained humanin, voltage-dependent anion-selective channel 1, and transcription factor A protein. Nuclear mitochondrial (NUMT) DNA complicated analyses of mitochondrial DNA (mtDNA), which otherwise suggested exosomes contain at most very low amounts of extended mtDNA sequences but likely contain degraded pieces of mtDNA. Cell and plasma-derived exosomes contained several mtDNA-derived mRNA sequences, including those for ND2, CO2, and humanin. These results can guide exosome-focused, mitochondria-pertinent biomarker development.
    Keywords:  NUMT; biomarker; exosome; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.mito.2020.09.006
  13. EBioMedicine. 2020 Sep 23. pii: S2352-3964(20)30390-X. [Epub ahead of print]60 103014
    Schlegel A, Muller X, Mueller M, Stepanova A, Kron P, de Rougemont O, Muiesan P, Clavien PA, Galkin A, Meierhofer D, Dutkowski P.
      BACKGROUND: Mitochondrial succinate accumulation has been suggested as key event for ischemia reperfusion injury in mice. No specific data are however available on behavior of liver mitochondria during ex situ machine perfusion in clinical transplant models.METHODS: We investigated mitochondrial metabolism of isolated perfused rat livers before transplantation. Livers were exposed to warm and cold ischemia to simulate donation after circulatory death (DCD) and organ transport. Subsequently, livers were perfused with oxygenated Belzer-MPS for 1h, at hypothermic or normothermic conditions. Various experiments were performed with supplemented succinate and/or mitochondrial inhibitors. The perfusate, liver tissues, and isolated mitochondria were analyzed by mass-spectroscopy and fluorimetry. Additionally, rat DCD livers were transplanted after 1h hypothermic or normothermic oxygenated perfusion. In parallel, perfusate samples were analysed during HOPE-treatment of human DCD livers before transplantation.
    FINDINGS: Succinate exposure during rat liver perfusion triggered a dose-dependent release of mitochondrial Flavin-Mononucleotide (FMN) and NADH in perfusates under normothermic conditions. In contrast, perfusate FMN was 3-8 fold lower under hypothermic conditions, suggesting less mitochondrial injury during cold re-oxygenation compared to normothermic conditions. HOPE-treatment induced a mitochondrial reprogramming with uploading of the nucleotide pool and effective succinate metabolism. This resulted in a clear superiority after liver transplantation compared to normothermic perfusion. Finally, the degree of mitochondrial injury during HOPE of human DCD livers, quantified by perfusate FMN and NADH, was predictive for liver function.
    INTERPRETATION: Mitochondrial injury determines outcome of transplanted rodent and human livers. Hypothermic oxygenated perfusion improves mitochondrial function, and allows viability assessment of liver grafts before implantation.
    FUNDING: detailed information can be found in Acknowledgments.
    Keywords:  Complex I; FMN; Hypothermic oxygenated perfusion; Liver transplantation; Normothermic oxygenated perfusion
    DOI:  https://doi.org/10.1016/j.ebiom.2020.103014
  14. J Cell Mol Med. 2020 Sep 30.
    Zhou R, Li S, Mei X, Jiang T, Wang Q.
      Ischaemia/reperfusion (I/R)-induced hepatic injury is regarded as a main reason of hepatic failure after transplantation or lobectomy. The current study aimed to investigate how the opioid analgesic remifentanil treatment affects I/R-induced hepatic injury and explore the possible mechanisms related to HIF1α. Initially, an I/R-induced hepatic injury animal model was established in C57BL/6 mice, and an in vitro hypoxia-reoxygenation model was constructed in NCTC-1469 cells, followed by remifentanil treatment and HIF1α silencing treatment. The levels of blood glucose, lipids, alanine transaminase (ALT) and aspartate transaminase (AST) in mouse serum were measured using automatic chemistry analyser, while the viability and apoptosis of cells were detected using CCK8 assay and flow cytometry. Our results revealed that mice with I/R-induced hepatic injury showed higher serum levels of blood glucose, lipids, ALT and AST and leukaemia inhibitory factor (LIF) expression, and lower HIF1α and ZEB1 expression (P < .05), which were reversed after remifentanil treatment (P < .05). Besides, HIF1α silencing increased the serum levels of blood glucose, lipids, ALT and AST (P < .05). Furthermore, hypoxia-induced NCTC-1469 cells exhibited decreased HIF1α and ZEB1 expression, reduced cell viability, as well as increased LIF expression and cell apoptosis (P < .05), which were reversed by remifentanil treatment (P < .05). Moreover, HIF1α silencing down-regulated ZEB1 expression, decreased cell viability, and increased cell apoptosis (P < .05). ZEB1 was identified to bind to the promoter region of LIF and inhibit its expression. In summary, remifentanil protects against hepatic I/R injury through HIF1α and downstream effectors.
    Keywords:  HIF1α; LIF; ZEB1; hepatic ischaemia/reperfusion injury; remifentanil
    DOI:  https://doi.org/10.1111/jcmm.15929
  15. PLoS One. 2020 ;15(10): e0240108
    Shimura T, Nakashiro C, Narao M, Ushiyama A.
      Dose assessment is an important issue for radiation emergency medicine to determine appropriate clinical treatment. Hematopoietic tissues are extremely vulnerable to radiation exposure. A decrease in blood cell count following radiation exposure is the first quantitative bio-indicator using hematological techniques. We further examined induction of oxidative stress biomarkers in residual lymphocytes to identify new biomarkers for dosimetry. In vivo whole-body radiation to mice exposed to 5 Gy significantly induces DNA double-strand breaks, which were visualized by γ-H2AX in mouse blood cells. Mouse blood smears and peripheral blood mononuclear cells (PBMC) isolated from irradiated mice were used for immunostaining for oxidative biomarkers, parkin or Nrf2. Parkin is the E3 ubiquitin ligase, which is normally localized in the cytoplasm, is relocated to abnormal mitochondria with low membrane potential (ΔΨm), where it promotes clearance via mitophagy. Nrf2 transcription factor controls the major cellular antioxidant responses. Both markers of oxidative stress were more sensitive and persistent over time than nuclear DNA damage. In conclusion, parkin and Nrf2 are potential biomarkers for use in radiation dosimetry. Identification of several biological markers which show different kinetics for radiation response is essential for radiation dosimetry that allows the assessment of radiation injury and efficacy of clinical treatment in emergency radiation incidents. Radiation-induced oxidative damage is useful not only for radiation dose assessment but also for evaluation of radiation risks on humans.
    DOI:  https://doi.org/10.1371/journal.pone.0240108
  16. Mol Cell Biochem. 2020 Sep 30.
    Cui Y, Pan M, Ma J, Song X, Cao W, Zhang P.
      Mitochondria have various cellular functions, including ATP synthesis, calcium homeostasis, cell senescence, and death. Mitochondrial dysfunction has been identified in a variety of disorders correlated with human health. Among the many underlying mechanisms of mitochondrial dysfunction, the opening up of the mitochondrial permeability transition pore (mPTP) is one that has drawn increasing interest in recent years. It plays an important role in apoptosis and necrosis; however, the molecular structure and function of the mPTP have still not been fully elucidated. In recent years, the abnormal opening up of the mPTP has been implicated in the development and pathogenesis of diverse diseases including ischemia/reperfusion injury (IRI), neurodegenerative disorders, tumors, and chronic obstructive pulmonary disease (COPD). This review provides a systematic introduction to the possible molecular makeup of the mPTP and summarizes the mitochondrial dysfunction-correlated diseases and highlights possible underlying mechanisms. Since the mPTP is an important target in mitochondrial dysfunction, this review also summarizes potential treatments, which may be used to inhibit pore opening up via the molecules composing mPTP complexes, thus suppressing the progression of mitochondrial dysfunction-related diseases.
    Keywords:  Mitochondrial dysfunction; Mitochondrial permeability transition pore (mPTP); Respiratory diseases; Translocator protein (TSPO); Tumor
    DOI:  https://doi.org/10.1007/s11010-020-03926-0
  17. Sci Rep. 2020 Sep 29. 10(1): 16041
    Bisbach CM, Hutto RA, Poria D, Cleghorn WM, Abbas F, Vinberg F, Kefalov VJ, Hurley JB, Brockerhoff SE.
      Rods and cones use intracellular Ca2+ to regulate many functions, including phototransduction and neurotransmission. The Mitochondrial Calcium Uniporter (MCU) complex is thought to be the primary pathway for Ca2+ entry into mitochondria in eukaryotes. We investigate the hypothesis that mitochondrial Ca2+ uptake via MCU influences phototransduction and energy metabolism in photoreceptors using a mcu-/- zebrafish and a rod photoreceptor-specific Mcu-/- mouse. Using genetically encoded Ca2+ sensors to directly examine Ca2+ uptake in zebrafish cone mitochondria, we found that loss of MCU reduces but does not eliminate mitochondrial Ca2+ uptake. Loss of MCU does not lead to photoreceptor degeneration, mildly affects mitochondrial metabolism, and does not alter physiological responses to light, even in the absence of the Na+/Ca2+, K+ exchanger. Our results reveal that MCU is dispensable for vertebrate photoreceptor function, consistent with its low expression and the presence of an alternative pathway for Ca2+ uptake into photoreceptor mitochondria.
    DOI:  https://doi.org/10.1038/s41598-020-72708-x