bims-mikwok 2021-08-15 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2021–08–15
eightteen papers selected by
Avinash N. Mukkala, University of Toronto

A DRP-1 dependent autophagy process facilitates rebuilding of the mitochondrial network and modulates adaptation capacity in response to acute heat stress during C. elegans development.
Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons.
Extracellular Mitochondrial Components and Effects on Cardiovascular Disease.
Understanding physiologic phospholipid maintenance in the context of brain mitochondrial phospholipid alterations after cardiac arrest.
Mitochondrial dynamics and mitophagy in lung disorders.
Hsp90 and its mitochondrial homologue TRAP-1 independently regulate hypoxia adaptations in Caenorhabditis elegans.
Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model.
Parkin-mediated mitochondrial quality control protects against aluminum-induced liver damage in mice.
Impairment of mitophagy and autophagy accompanies calcific aortic valve stenosis favoring cell death and the severity of disease.
MicroRNA-128 inhibits mitochondrial biogenesis and function via targeting PGC1α and NDUFS4.
3D neuronal mitochondrial morphology in axons, dendrites, and somata of the aging mouse hippocampus.
Mitochondrial dysfunction associated with autophagy and mitophagy in cerebrospinal fluid cells of patients with delayed cerebral ischemia following subarachnoid hemorrhage.
NDP52 Protects against Myocardial Infarction-Provoked Cardiac Anomalies through Promoting Autophagosome-Lysosome Fusion via Recruiting TBK1 and RAB7.
Defining the molecular mechanisms of the mitochondrial permeability transition through genetic manipulation of F-ATP synthase.
Advances in Mitochondrial Medicine and Translational Research.
Hexokinases inhibit death receptor-dependent apoptosis on the mitochondria.
New insights into mitophagy and stem cells.
Intercellular Transfer of Mitochondria between Senescent Cells through Cytoskeleton-Supported Intercellular Bridges Requires mTOR and CDC42 Signalling.

Autophagy. 2021 Aug 12. 1-2

A DRP-1 dependent autophagy process facilitates rebuilding of the mitochondrial network and modulates adaptation capacity in response to acute heat stress during C. elegans development.

Yanfang Chen, Emmanuel Culetto, Renaud Legouis.

  Temperature variations induce stressful conditions that challenge the ability of organisms to maintain cell homeostasis. The intensity and duration of heat stress affect cell response very differently, ranging from a beneficial effect - hormesis - to necrotic cell death. There is a strong interplay between the cell response to heat shock and macroautophagy/autophagy, which is induced to cope with stress. Using Caenorhabditis elegans, we developed a new paradigm to study adaptation to acute non-lethal heat-stress (aHS) during development. We found that aHS results in transient fragmentation of mitochondria, decreased cellular respiration, and delayed development. Moreover, an active autophagy flux associated with mitophagy events is triggered in many tissues, enables the rebuilding of the mitochondrial network and modulates the adaptive plasticity of the development, showing that the autophagic response is protective for C. elegans. Using genetic and cellular approaches, we showed that mitochondria are a major site for autophagosome biogenesis in the epidermis, under both standard and heat-stress conditions. We determined that DRP-1 (Dynamin-Related Protein 1) involved in mitochondrial fission, is an important player for the autophagy process and the adaptation to aHS. Our study suggests that DRP-1 is involved in coordinating mitochondrial fission and autophagosome biogenesis during stress.

Keywords:  Autophagy; C. elegans; DRP-1; development plasticity; heat shock; mitochondria

DOI:  https://doi.org/10.1080/15548627.2021.1953821
PLoS Genet. 2021 Aug 12. 17(8): e1009731

Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons.

Ryan Insolera, Péter Lőrincz, Alec J Wishnie, Gábor Juhász, Catherine A Collins.

A healthy population of mitochondria, maintained by proper fission, fusion, and degradation, is critical for the long-term survival and function of neurons. Here, our discovery of mitophagy intermediates in fission-impaired Drosophila neurons brings new perspective into the relationship between mitochondrial fission and mitophagy. Neurons lacking either the ataxia disease gene Vps13D or the dynamin related protein Drp1 contain enlarged mitochondria that are engaged with autophagy machinery and also lack matrix components. Reporter assays combined with genetic studies imply that mitophagy both initiates and is completed in Drp1 impaired neurons, but fails to complete in Vps13D impaired neurons, which accumulate compromised mitochondria within stalled mito-phagophores. Our findings imply that in fission-defective neurons, mitophagy becomes induced, and that the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation.

DOI: https://doi.org/10.1371/journal.pgen.1009731
DNA Cell Biol. 2021 Aug 07.

Extracellular Mitochondrial Components and Effects on Cardiovascular Disease.

Yu Xu, Yanhua Yu, Bowen Yang, Jingjiao Hui, Cai Zhang, Hua Fang, Xiaoyun Bian, Min Tao, Yipeng Lu, Zhenglu Shang.

  Besides being powerhouses of the cell, mitochondria released into extracellular space act as intercellular signaling. Mitochondria and their components mediate cell-to-cell communication in free form or embedded in a carrier. The pathogenesis of cardiovascular disease is complex, which shows close relationship with inflammation and metabolic abnormalities. Since mitochondria sustain optimal function of the heart, extracellular mitochondria are emerging as a key regulator in the development of cardiovascular disease. In this review, we provide recent findings in the presence and forms of mitochondria transfer between cells, as well as the effects of these mitochondria on vascular inflammation and ischemic myocardium. Mitochondrial transplantation is a novel treatment paradigm for patients suffering from acute cardiovascular accident and challenges the traditional methods of mitochondria isolation.

Keywords:  extracellular vesicles; free circulating mitochondria DNA; inflammation; mitochondria; mitochondrial transplantation

DOI:  https://doi.org/10.1089/dna.2021.0087
Mitochondrion. 2021 Aug 09. pii: S1567-7249(21)00110-0. [Epub ahead of print]

Understanding physiologic phospholipid maintenance in the context of brain mitochondrial phospholipid alterations after cardiac arrest.

Cyrus E Kuschner, Nancy Kim, Muhammad Shoaib, Rishabh C Choudhary, Mitsuaki Nishikimi, Tai Yin, Lance B Becker, Charles L Hoppel, Junhwan Kim.

  Cardiac arrest (CA) induces whole-body ischemia resulting in mitochondrial dysfunction. We used isolated mitochondria to examine phospholipid alterations in the brain, heart, kidney, and liver post-CA. Our data shows that ischemia/reperfusion most significantly alters brain mitochondria phospholipids, predominately after resuscitation. Furthermore, the alterations do not appear to be a function of dysregulated importation of phospholipids, but caused by impaired intra-mitochondrial synthesis and/or remodeling of phospholipids. Our data demonstrates only brain mitochondria undergo significant alterations in phospholipids, providing a rationale for the high vulnerability of the brain to ischemia/reperfusion. Furthermore, analyzing this pathophysiologic state provides insight into physiologic mitochondrial phospholipid metabolism.

Keywords:  Cardiac arrest; Cardiolipin; Ischemia-reperfusion injury; Mitochondria; mass spectrometry

DOI:  https://doi.org/10.1016/j.mito.2021.08.009
Life Sci. 2021 Aug 10. pii: S0024-3205(21)00863-8. [Epub ahead of print] 119876

Mitochondrial dynamics and mitophagy in lung disorders.

Archana Sharma, Shaniya Ahmad, Tanveer Ahmad, Shakir Ali, Mansoor Ali Syed.

  Mitochondria are biosynthetic, bioenergetic, and signaling organelles which are critical for physiological adaptations and cellular stress responses to the environment. Various endogenous and environmental stress affects critical processes in mitochondrial homeostasis such as oxidative phosphorylation, biogenesis, mitochondrial redox system which leads to the formation of reactive oxygen species (ROS) and free radicals. The state of function of the mitochondrion is particularly dependent on the dynamic balance between mitochondrial biogenesis, fusion and fission, and degradation of damaged mitochondria by mitophagy. Increasing evidence has suggested a prominent role of mitochondrial dysfunction in the onset and progression of various lung pathologies, ranging from acute to chronic disorders. In this comprehensive review, we discuss the emerging findings of multifaceted regulations of mitochondrial dynamics and mitophagy in normal lung homeostasis as well as the prominence of mitochondrial dysfunction as a determining factor in different lung disorders such as lung cancer, COPD, IPF, ALI/ARDS, BPD, and asthma. The review will contribute to the existing understanding of critical molecular machinery regulating mitochondrial dynamic state during these pathological states. Furthermore, we have also highlighted various molecular checkpoints involved in mitochondrial dynamics, which may serve as hopeful therapeutic targets for the development of potential therapies for these lung disorders.

Keywords:  Lung disorders; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mitophagy

DOI:  https://doi.org/10.1016/j.lfs.2021.119876
Mitochondrion. 2021 Aug 05. pii: S1567-7249(21)00103-3. [Epub ahead of print]

Hsp90 and its mitochondrial homologue TRAP-1 independently regulate hypoxia adaptations in Caenorhabditis elegans.

Aakanksha Pant, Keerthi Chittayil Krishnakumar, Navyamol Chakkalaparambil Dileep, Meghana Yamana, Narayanan Meenakshisundaran Alamelu, Paithankar Khanderao, Vijayalakshmi Amash, Sreedhar Amere Subbarao.

  Mitochondrial adaptations to various environmental cues contribute to cellular and organismal adaptations across multiple model organisms. Due to increased complexity, a direct connection between mitochondrial integrity and oxygen fluctuations, and survival fitness was not demonstrated. Here, using C. elegans as a model system, we studied the role of HIF-1, Hsp90, and TRAP-1 in mitochondrial adaptations during chemical hypoxia. We show that Hsp90mt (Hsp90 mutant) but not HIF-1mt (HIF-1 mutant) affects hypoxia adaptation in nematodes. TRAP-1KD (TRAP-1 knockdown) worms interfered with the survival and fecundity of worms. Compared to Hsp90mt, TRAP-1KD has induced a significant decrease in mitochondrial integrity and oxygen consumption rate. The complex I inhibitor rotenone did not affect ATP levels in Hsp90mt worms. However, ATP levels were decreased in TRAP-1KD worms under similar conditions. The glucose restriction has reduced, and glucose supplementation has increased the survival rate in Hsp90mt worms. Neither glucose restriction nor glucose supplementation has significantly affected the survival of TRAP-1KD worms in response to hypoxia. However, TRAP-1 inhibition using a nanocarrier drug has dramatically reduced the survival rate in response to hypoxia. Our results suggest that Hsp90 and TRAP-1 independently regulate hypoxia adaptations and metabolic plasticity in C. elegans. Considering the emerging roles of TRAP-1 in altered energy metabolism and cellular adaptations, our findings gain importance.

Keywords:  Caenorhabditis elegans; HIF-1; Hsp90; TRAP-1; hypoxia; mitochondria

DOI:  https://doi.org/10.1016/j.mito.2021.08.002
Ann Surg. 2021 Aug 13.

Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model.

Joohyun Kim, Michael A Zimmerman, Woo Young Shin, Brent T Boettcher, Ju-Seog Lee, Jong-In Park, Muhammed Ali, Meiying Yang, Jyotsna Mishra, Catherine E Hagen, Joseph E McGraw, Angela Mathison, Harvey J Woehlck, Gwen Lomberk, Amadou K S Camara, Raul A Urrutia, David F Stowe, Johnny C Hong.

OBJECTIVE: We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death (DCD) model.
SUMMARY OF BACKGROUND DATA: DCD represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation.
METHODS: Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control-Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed.
RESULTS: Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis.
CONCLUSION: Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Subnormothermic RHR has potential applicability to clinical liver transplantation.

DOI: https://doi.org/10.1097/SLA.0000000000005156
Food Chem Toxicol. 2021 Aug 08. pii: S0278-6915(21)00518-4. [Epub ahead of print]156 112485

Parkin-mediated mitochondrial quality control protects against aluminum-induced liver damage in mice.

Bonan Xiao, Yilong Cui, Yuping Wang, Menglin Liu, Pengli Liu, Jian Zhang, Xuliang Zhang, Miao Song, Yanfei Han, Yanfei Li.

  Aluminum (Al) is known to be hepatotoxic. Oxidative stress is the main mechanism of liver injury caused by Al, and can also lead to mitochondrial damage. Mitochondrial damage is a prerequisite for mitochondrial quality control (MQC) dysregulation. Parkin can activate MQC and maintain mitochondrial homeostasis. However, the role of Parkin-mediated MQC in Al-induced liver damage has not been elucidated. In this study, forty male wild type (WT) C57BL/6N mice were treated with 0, 44.825, 89.65 or 179.3 mg/kg body weight AlCl3 in drinking water for 90 days, respectively. We found that Al induced mitophagy and disrupted mitochondrial dynamics and mitochondrial biogenesis. Then, twenty male WT C57BL/6N mice and twenty male Parkin knockout (Parkin-/-) C57BL/6N mice were divided into four groups and treated with 0, 89.65, 0, 89.65 mg/kg body weight AlCl3 in drinking water for 90 days, respectively. We found that Parkin-/- inhibited mitophagy and further disrupted mitochondrial dynamics and mitochondrial biogenesis. These results indicated that Parkin-mediated MQC could be disrupted by Al and protected against Al-induced liver damage.

Keywords:  Aluminum (Al); Liver; Mice; Mitochondrial quality control; Parkin

DOI:  https://doi.org/10.1016/j.fct.2021.112485
Cardiovasc Res. 2021 Aug 10. pii: cvab267. [Epub ahead of print]

Impairment of mitophagy and autophagy accompanies calcific aortic valve stenosis favoring cell death and the severity of disease.

Giampaolo Morciano, Simone Patergnani, Gaia Pedriali, Paolo Cimaglia, Elisa Mikus, Simone Calvi, Alberto Albertini, Carlotta Giorgi, Gianluca Campo, Roberto Ferrari, Paolo Pinton.

   AIMS: In the last 15 years, some observations tried to shed light on the dysregulation of the cellular self-digestion process in calcific aortic valve stenosis (CAVS), but the results obtained remain still controversial. This work is aimed to definitively establish the trend of autophagy in patients affected by CAVS, to analyze the putative involvement of other determinants which impact on the mitochondrial quality control mechanisms and to explore possible avenues for pharmacological interventions in the treatment of CAVS.
METHODS AND RESULTS: This observational study, performed exclusively in ex vivo human samples (cells and serum), by using biochemical approaches and correlations with clinical data, describes new biological features of the calcified valve in terms of mitochondrial dysfunctions. In detail, we unveiled a significant deficiency in mitochondrial respiration and in ATP production coupled to increased production of lactates. In addition, mitochondrial population in the pathologic group is aged with significant alterations in biogenesis and mitophagy pathways. We are also reporting an updated view about autophagy accompanying the calcification process and advanced stages of the disease. We provided evidence for a rapamycin-based therapeutic strategy to revert the calcified phenotype to the wild type one.
CONCLUSIONS: Our data suggest that the Calcific Aortic Valve Stenosis phenotype is featured by defects in mitochondrial quality control mechanisms and that autophagy is not activated enough to counteract cell death and sustain cell functions. Thus, boosting autophagy and mitophagy from short to long-term revert quite all pathological phenotypes.
TRANSLATIONAL PERSPECTIVE: The findings from this study provide evidence for new molecular targets involving mitochondrial quality control mechanisms becoming dysregulated in CAVS. These pathways should be considered as amenable for a combination of new therapies in humans for three reasons: i) no pharmacological treatments are still available to slow down the development of advanced CAVS, ii) being calcification a recurring pathway and iii) the targets proposed are druggable by existing drugs used in the clinic for different purposes. This work also suggests a serum biomarker to be highly related to the stage of disease and the calcification grade of the valve.

Keywords:  aortic stenosis; autophagy; calcification; mitochondria; mitophagy

DOI:  https://doi.org/10.1093/cvr/cvab267
Mitochondrion. 2021 Aug 09. pii: S1567-7249(21)00109-4. [Epub ahead of print]

MicroRNA-128 inhibits mitochondrial biogenesis and function via targeting PGC1α and NDUFS4.

Kritika Sharma, Amit Chandra, Yasha Hasija, Neeru Saini.

  The size and morphology of mitochondria are very heterogeneous and correlates well with their healthy functioning. In many pathological conditions, mitochondrial morphology is altered due to impaired mitochondrial dynamics (a collective term for mitochondrial fusion and fission) and dysfunction. The current study aimed at identifying the role of microRNA-128 (miR-128) in regulating mitochondrial biogenesis. Previously, peroxisome proliferator activator receptor γ coactivator 1α (PGC1α) has been shown to co-activate key intermediates of mitochondrial biogenesis, function, and dynamics; however, the upstream regulatory network remains largely unknown. We, herein using in silico analysis followed by in vitro experiments in C2C12 myoblasts, showed that miR-128 reduces mitochondrial biogenesis by directly targeting PGC1α. The expression of downstream genes, nuclear respiratory factors 1 and 2 (NRF1 and NRF2, respectively), and mitochondrial transcription factor A (TFAM) were decreased in C2C12 myoblasts upon overexpression of miR-128. Also, miR-128 is shown to promote mitochondrial dysfunction by directly targeting NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (NDUFS4). The mitochondrial dynamics and morphology were impaired post miR-128 overexpression, as revealed by downregulation of fusion proteins (mitofusin1 and 2, i.e., MFN1 and MFN2, respectively) and upregulation of fission protein (dynamin-related protein 1, i.e., DRP1). Conversely, inhibition of miR-128 expression improved mitochondrial biogenesis, function, and dynamics, as evidenced by increased mitochondrial mass and ATP production after antimiR-128 treatment. Our findings reveal that inhibition of miR-128 can be a new potential target for reversing the effects of metabolic disorders of skeletal muscle as observed during many pathophysiological conditions such as obesity and type II diabetes.

Keywords:  MiR-128; NDUFS4; PGC1α; mitochondrial biogenesis; mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.mito.2021.08.008
Cell Rep. 2021 Aug 10. pii: S2211-1247(21)00939-6. [Epub ahead of print]36(6): 109509

3D neuronal mitochondrial morphology in axons, dendrites, and somata of the aging mouse hippocampus.

Julie Faitg, Clay Lacefield, Tracey Davey, Kathryn White, Ross Laws, Stylianos Kosmidis, Amy K Reeve, Eric R Kandel, Amy E Vincent, Martin Picard.

  The brain's ability to process complex information relies on the constant supply of energy through aerobic respiration by mitochondria. Neurons contain three anatomically distinct compartments-the soma, dendrites, and projecting axons-which have different energetic and biochemical requirements, as well as different mitochondrial morphologies in cultured systems. In this study, we apply quantitative three-dimensional electron microscopy to map mitochondrial network morphology and complexity in the mouse brain. We examine somatic, dendritic, and axonal mitochondria in the dentate gyrus and cornu ammonis 1 (CA1) of the mouse hippocampus, two subregions with distinct principal cell types and functions. We also establish compartment-specific differences in mitochondrial morphology across these cell types between young and old mice, highlighting differences in age-related morphological recalibrations. Overall, these data define the nature of the neuronal mitochondrial network in the mouse hippocampus, providing a foundation to examine the role of mitochondrial morpho-function in the aging brain.

Keywords:  3D reconstruction; SBF-SEM; aging; hippocampus; microscopy; mitochondria; morphology; morphometry; three-dimensional; topology

DOI:  https://doi.org/10.1016/j.celrep.2021.109509
Sci Rep. 2021 Aug 13. 11(1): 16512

Mitochondrial dysfunction associated with autophagy and mitophagy in cerebrospinal fluid cells of patients with delayed cerebral ischemia following subarachnoid hemorrhage.

Dong Hyuk Youn, Youngmi Kim, Bong Jun Kim, Myeong Seon Jeong, Jooeun Lee, Jong Kook Rhim, Heung Cheol Kim, Jin Pyeong Jeon.

Decreased mitochondrial membrane potential in cerebrospinal fluid (CSF) was observed in patients with subarachnoid hemorrhage (SAH) accompanied by delayed cerebral ischemia (DCI). However, whether abnormal mechanisms of mitochondria are associated with the development of DCI has not been reported yet. Under cerebral ischemia, mitochondria can transfer into the extracellular space. Mitochondrial dysfunction can aggravate neurologic complications. The objective of this study was to evaluate whether mitochondrial dysfunction might be associated with autophagy and mitophagy in CSF cells to provide possible insight into DCI pathogenesis. CSF samples were collected from 56 SAH patients (DCI, n = 21; and non-DCI, n = 35). We analyzed CSF cells using autophagy and mitophagy markers (DAPK1, BNIP3L, BAX, PINK1, ULK1, and NDP52) via qRT-PCR and western blotting of proteins (BECN1, LC3, and p62). Confocal microscopy and immunogold staining were performed to demonstrate the differentially expression of markers within dysfunctional mitochondria. Significant induction of autophagic flux with accumulation of autophagic vacuoles, increased expression of BECN1, LC3-II, and p62 degradation were observed during DCI. Compared to non-DCI patients, DCI patients showed significantly increased mRNA expression levels (2-ΔCt) of DAPK1, BNIP3L, and PINK1, but not BAX, ULK1, or NDP52. Multivariable logistic regression analysis revealed that Hunt and Hess grade ≥ IV (p = 0.023), DAPK1 (p = 0.003), and BNIP3L (p = 0.039) were related to DCI. Increased mitochondrial dysfunction associated with autophagy and mitophagy could play an important role in DCI pathogenesis.

DOI: https://doi.org/10.1038/s41598-021-96092-2
Antioxid Redox Signal. 2021 Aug 12.

NDP52 Protects against Myocardial Infarction-Provoked Cardiac Anomalies through Promoting Autophagosome-Lysosome Fusion via Recruiting TBK1 and RAB7.

Mingming Sun, Wenjing Zhang, Yaguang Bi, Haixia Xu, Miyesaier Abudureyimu, Hu Peng, Yingmei Zhang, Jun Ren.

AIMS: Acute myocardial infarction (MI), caused by acute coronary artery obstruction, is a common cardiovascular event leading to mortality. Nuclear dot protein 52 (NDP52) is an essential selective autophagy adaptor, although its function in MI is still obscure. This study was designed to examine the function of NDP52 in MI and the associated mechanisms.
RESULTS: Our results revealed that MI challenge overtly impaired myocardial geometry and systolic function, along with cardiomyocyte apoptosis, myocardial interstitial fibrosis, and mitochondrial damage, and NDP52 nullified such devastating responses. Further studies showed the blockade of mitochondrial clearance is related to MI-induced buildup of damaged mitochondria. Mechanistic approaches depicted that 7-day MI induced abnormal mitophagy flux, resulting in poor lysosomal clearance of injured mitochondria. NDP52 promoted mitophagy flux through recruitment of RAB7 and TBK1. Upon protein colocalization, TBK1 phosphorylated RAB7, in line with the finding that chloroquine or a TBK1 inhibitor reversed NDP52-dependent beneficial responses.
INNOVATION: This study denoted a novel mechanism that NDP52 promotes cardioprotection against ischemic heart diseases through interaction with TBK1 and RAB7, leading to RAB7 phosphorylation, induction of mitophagy to clear ischemia-induced impaired mitochondria, thus preventing cardiomyocyte apoptosis in MI.
CONCLUSION: Our results indicate that NDP52 promotes autophagic flux and clears damaged mitochondria to diminish ROS and cell death in a TBK1/RAB7-dependent manner and thus limits MI induced injury.

DOI: https://doi.org/10.1089/ars.2020.8253
Nat Commun. 2021 08 10. 12(1): 4835

Defining the molecular mechanisms of the mitochondrial permeability transition through genetic manipulation of F-ATP synthase.

Andrea Carrer, Ludovica Tommasin, Justina Šileikytė, Francesco Ciscato, Riccardo Filadi, Andrea Urbani, Michael Forte, Andrea Rasola, Ildikò Szabò, Michela Carraro, Paolo Bernardi.

F-ATP synthase is a leading candidate as the mitochondrial permeability transition pore (PTP) but the mechanism(s) leading to channel formation remain undefined. Here, to shed light on the structural requirements for PTP formation, we test cells ablated for g, OSCP and b subunits, and ρ0 cells lacking subunits a and A6L. Δg cells (that also lack subunit e) do not show PTP channel opening in intact cells or patch-clamped mitoplasts unless atractylate is added. Δb and ΔOSCP cells display currents insensitive to cyclosporin A but inhibited by bongkrekate, suggesting that the adenine nucleotide translocator (ANT) can contribute to channel formation in the absence of an assembled F-ATP synthase. Mitoplasts from ρ0 mitochondria display PTP currents indistinguishable from their wild-type counterparts. In this work, we show that peripheral stalk subunits are essential to turn the F-ATP synthase into the PTP and that the ANT provides mitochondria with a distinct permeability pathway.

DOI: https://doi.org/10.1038/s41467-021-25161-x
Mitochondrion. 2021 Aug 04. pii: S1567-7249(21)00102-1. [Epub ahead of print]

Advances in Mitochondrial Medicine and Translational Research.

Raviprasad Kuthethur, Keshava Prasad, Sanjiban Chakrabarty, Shama Prasada Kabekkodu, Keshav K Singh, Kumarasamy Thangaraj, Kapaettu Satyamoorthy.

  Current knowledge of mitochondrial biology and function has provided with tools and technologies that helped a better understanding of the molecular etiology of complex mitochondrial disorders. Dual genetic control of this subcellular organelle function regulates various signaling mechanisms which are essential for metabolism, bioenergetics, fatty acid biosynthesis, and DNA replication & repair. Understanding nuclear mitochondrial crosstalk through advanced genomics as well as clinical perspectives is the overall basis of mitochondrial research and medicine, also the sole objective of Society for Mitochondrial Medicine and Research (SMRM) - India. The eighth virtual international conference on 'Advances in Mitochondrial Medicine and Translational Research' was organized at the Manipal School of Life Sciences, MAHE, Manipal, India, during 6 - 7 November 2020. The aim of the virtual conference was to highlight the recent advances and future perspectives that represent comprehensive clinical and fundamental research interests in the area of mitochondrial biology of human diseases. To systematically present the various findings in mitochondrial biology, the meeting was themed with specific aspects comprising (a) mitochondrial disorders: clinical & genomic perspectives, (b) mitochondria in cancer, (c) mitochondrial metabolism & disorders, and (d) mitochondrial diseases & therapy. This report provides an overview of the recent advancements in the area of mitochondrial biology and medicine that was discussed at the conference.

Keywords:  Anterograde and retrograde signaling; Cancer and mitochondria; Mitochondrial disorders; Mitochondrial metabolism; Therapeutics and mitochondria; miRNAs and mitochondria

DOI:  https://doi.org/10.1016/j.mito.2021.08.001
Proc Natl Acad Sci U S A. 2021 Aug 17. pii: e2021175118. [Epub ahead of print]118(33):

Hexokinases inhibit death receptor-dependent apoptosis on the mitochondria.

Joachim Lauterwasser, Franziska Fimm-Todt, Aline Oelgeklaus, Annabell Schreiner, Kathrin Funk, Hugo Falquez-Medina, Ramona Klesse, Günther Jahreis, Ralf M Zerbes, Katelyn O'Neill, Martin van der Laan, Xu Luo, Frank Edlich.

  Death receptor-mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling, the truncated BH3-only protein BID can activate the proapoptotic BCL-2 proteins BAX and BAK and trigger the permeabilization of the mitochondria. BAX and BAK are inhibited by prosurvival BCL-2 proteins through retrotranslocation from the mitochondria into the cytosol, but a specific resistance mechanism to truncated BID-dependent apoptosis is unknown. Here, we report that hexokinase 1 and hexokinase 2 inhibit the apoptosis activator truncated BID as well as the effectors BAX and BAK by retrotranslocation from the mitochondria into the cytosol. BCL-2 protein shuttling and protection from TRAIL- and FasL-induced cell death requires mitochondrial hexokinase localization and interactions with the BH3 motifs of BCL-2 proteins but not glucose phosphorylation. Together, our work establishes hexokinase-dependent retrotranslocation of truncated BID as a selective protective mechanism against death receptor-induced apoptosis on the mitochondria.

Keywords:  BCL-2 proteins; BH3-only proteins; apoptosis

DOI:  https://doi.org/10.1073/pnas.2021175118
Stem Cell Res Ther. 2021 Aug 11. 12(1): 452

New insights into mitophagy and stem cells.

Qingyin Lin, Jiaqi Chen, Lifang Gu, Xingang Dan, Cheng Zhang, Yanzhou Yang.

  Mitophagy is a specific autophagic phenomenon in which damaged or redundant mitochondria are selectively cleared by autophagic lysosomes. A decrease in mitophagy can accelerate the aging process. Mitophagy is related to health and longevity and is the key to protecting stem cells from metabolic stress damage. Mitophagy decreases the metabolic level of stem cells by clearing active mitochondria, so mitophagy is becoming increasingly necessary to maintain the regenerative capacity of old stem cells. Stem cell senescence is the core problem of tissue aging, and tissue aging occurs not only in stem cells but also in transport amplifying cell chambers and the stem cell environment. The loss of the autophagic ability of stem cells can cause the accumulation of mitochondria and the activation of the metabolic state as well as damage the self-renewal ability and regeneration potential of stem cells. However, the claim remains controversial. Mitophagy is an important survival strategy against nutrient deficiency and starvation, and mitochondrial function and integrity may affect the viability, proliferation and differentiation potential, and longevity of normal stem cells. Mitophagy can affect the health and longevity of the human body, so the number of studies in this field has increased, but the mechanism by which mitophagy participates in stem cell development is still not fully understood. This review describes the potential significance of mitophagy in stem cell developmental processes, such as self-renewal, differentiation and aging. Through this work, we discovered the role and mechanism of mitophagy in different types of stem cells, identified novel targets for killing cancer stem cells and curing cancer, and provided new insights for future research in this field.

Keywords:  Autophagy; Cancer stem cells; Mitochondria; Mitophagy; Stem cells

DOI:  https://doi.org/10.1186/s13287-021-02520-5
Oxid Med Cell Longev. 2021 ;2021 6697861

Intercellular Transfer of Mitochondria between Senescent Cells through Cytoskeleton-Supported Intercellular Bridges Requires mTOR and CDC42 Signalling.

Hannah E Walters, Lynne S Cox.

Cellular senescence is a state of irreversible cell proliferation arrest induced by various stressors including telomere attrition, DNA damage, and oncogene induction. While beneficial as an acute response to stress, the accumulation of senescent cells with increasing age is thought to contribute adversely to the development of cancer and a number of other age-related diseases, including neurodegenerative diseases for which there are currently no effective disease-modifying therapies. Non-cell-autonomous effects of senescent cells have been suggested to arise through the SASP, a wide variety of proinflammatory cytokines, chemokines, and exosomes secreted by senescent cells. Here, we report an additional means of cell communication utilised by senescent cells via large numbers of membrane-bound intercellular bridges-or tunnelling nanotubes (TNTs)-containing the cytoskeletal components actin and tubulin, which form direct physical connections between cells. We observe the presence of mitochondria in these TNTs and show organelle transfer through the TNTs to adjacent cells. While transport of individual mitochondria along single TNTs appears by time-lapse studies to be unidirectional, we show by differentially labelled co-culture experiments that organelle transfer through TNTs can occur between different cells of equivalent cell age, but that senescent cells, rather than proliferating cells, appear to be predominant mitochondrial donors. Using small molecule inhibitors, we demonstrate that senescent cell TNTs are dependent on signalling through the mTOR pathway, which we further show is mediated at least in part through the downstream actin-cytoskeleton regulatory factor CDC42. These findings have significant implications for the development of senomodifying therapies, as they highlight the need to account for local direct cell-cell contacts as well as the SASP in order to treat cancer and diseases of ageing in which senescence is a key factor.

DOI: https://doi.org/10.1155/2021/6697861