bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022–01–16
eightteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Mitochondria shed their outer membrane in response to infection-induced stress.
  2. Mosaic dysfunction of mitophagy in mitochondrial muscle disease.
  3. NHR-80 senses the mitochondrial UPR to rewire citrate metabolism for lipid accumulation in Caenorhabditis elegans.
  4. Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis.
  5. Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase.
  6. DRP1 interacts directly with BAX to induce its activation and apoptosis.
  7. Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes.
  8. Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer's disease.
  9. SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics.
  10. Ulk1-dependent alternative mitophagy plays a protective role during pressure overload in the heart.
  11. Alternative mitophagy is a major form of mitophagy in the chronically stressed heart.
  12. GAK and PRKCD kinases regulate basal mitophagy.
  13. RABEP1/Rabaptin5: a link between autophagy and early endosome homeostasis.
  14. Ceramide-induced mitophagy impairs ß-oxidation-linked energy production in PINK1 deficiency.
  15. Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia.
  16. Absence of Cardiolipin From the Outer Leaflet of a Mitochondrial Inner Membrane Mimic Restricts Opa1-Mediated Fusion.
  17. Targeting and Insertion of Membrane Proteins in Mitochondria.
  18. Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis.
  1. Science. 2022 Jan 14. 375(6577): eabi4343
    Mitochondria shed their outer membrane in response to infection-induced stress.
    Xianhe Li, Julian Straub, Tânia Catarina Medeiros, Chahat Mehra, Fabian den Brave, Esra Peker, Ilian Atanassov, Katharina Stillger, Jonas Benjamin Michaelis, Emma Burbridge, Colin Adrain, Christian Münch, Jan Riemer, Thomas Becker, Lena F Pernas.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abi4343
  2. Cell Metab. 2022 Jan 07. pii: S1550-4131(21)00636-7. [Epub ahead of print]
    Mosaic dysfunction of mitophagy in mitochondrial muscle disease.
    Takayuki Mito, Amy E Vincent, Julie Faitg, Robert W Taylor, Nahid A Khan, Thomas G McWilliams, Anu Suomalainen.
      Mitophagy is a quality control mechanism that eliminates damaged mitochondria, yet its significance in mammalian pathophysiology and aging has remained unclear. Here, we report that mitophagy contributes to mitochondrial dysfunction in skeletal muscle of aged mice and human patients. The early disease stage is characterized by muscle fibers with central nuclei, with enhanced mitophagy around these nuclei. However, progressive mitochondrial dysfunction halts mitophagy and disrupts lysosomal homeostasis. Interestingly, activated or halted mitophagy occur in a mosaic manner even in adjacent muscle fibers, indicating cell-autonomous regulation. Rapamycin restores mitochondrial turnover, indicating mTOR-dependence of mitochondrial recycling in advanced disease stage. Our evidence suggests that (1) mitophagy is a hallmark of age-related mitochondrial pathology in mammalian muscle, (2) mosaic halting of mitophagy is a mechanism explaining mosaic respiratory chain deficiency and accumulation of pathogenic mtDNA variants in adult-onset mitochondrial diseases and normal aging, and (3) augmenting mitophagy is a promising therapeutic approach for muscle mitochondrial dysfunction.
    Keywords:  SBFSEM; centrally nucleated fibers; lysosome; mito-QC; mitochondrial disease; mitochondrial myopathy; mitophagy; patient; ragged-red fibers
    DOI:  https://doi.org/10.1016/j.cmet.2021.12.017
  3. Cell Rep. 2022 Jan 11. pii: S2211-1247(21)01710-1. [Epub ahead of print]38(2): 110206
    NHR-80 senses the mitochondrial UPR to rewire citrate metabolism for lipid accumulation in Caenorhabditis elegans.
    Rendan Yang, Yamei Li, Yanli Wang, Jingjing Zhang, Qijing Fan, Jianlin Tan, Weizhen Li, Xiaoju Zou, Bin Liang.
      Mitochondria are known as the powerhouse of the cell. Dysfunction of mitochondria homeostasis induces the mitochondrial unfolded protein response (UPRmt), altering cellular metabolism. How cells sense the UPRmt to rewire metabolism is largely unknown. Here, we show that inactivation of either the citric/tricarboxylic acid (TCA) cycle enzymes aco-2 or idha-1, which encode aconitase and isocitrate dehydrogenase respectively, leads to citrate accumulation. In Caenorhabditis elegans, both in vitro and in vivo, citrate accumulation consequently triggers the UPRmt and also promotes lipid accumulation. The transcription factor DVE-1 binds to the promoter of the nuclear hormone receptor nhr-80 to transactivate its expression. NHR-80 then upregulates lipogenesis and lipid accumulation, shifting excess citrate for use in lipogenesis and for storage as triacylglycerol in lipid droplets. Inactivation of DVE-1 or NHR-80 fully abolishes the citrate-induced lipid accumulation. Therefore, our work uncovers a DVE-1-NHR-80-lipogenesis axis linking the transmission of the mitochondrial stress signal to lipid metabolism.
    Keywords:  citrate; citric/tricarboxylic acid (TCA) cycle; lipid accumulation; mitochondrial unfolded protein response (UPR(mt)); nuclear hormone receptor NHR-80
    DOI:  https://doi.org/10.1016/j.celrep.2021.110206
  4. JCI Insight. 2022 Jan 11. pii: e150041. [Epub ahead of print]
    Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis.
    Yae-Huei Liou, Jean Personnaz, David Jacobi, Nelson H Knudsen, Mayer M Chalom, Kyle A Starost, Israel C Nnah, Chih-Hao Lee.
      Mitophagy and mitochondrial integrated stress response (ISR) are two primary protective mechanisms to maintain functional mitochondria. Whether these two processes are coordinately regulated remains unclear. Here we show that mitochondrial fission 1 protein (Fis1), which is required for completion of mitophagy, serves as a signaling hub linking mitophagy and ISR. In mouse hepatocytes, high fat diet (HFD) feeding induces unresolved oxidative stress, defective mitophagy and enhanced type I interferon (IFN-I) response implicated in promoting metabolic inflammation. Adenoviral-mediated acute hepatic Fis1 over-expression is sufficient to reduce oxidative damage and improve glucose homeostasis in HFD fed mice. RNA-seq analysis reveals that Fis1 triggers a retrograde mitochondria-to-nucleus communication upregulating ISR genes encoding anti-oxidant defense, redox homeostasis and proteostasis pathways. Fis1-mediated ISR also suppresses expression of IFN-I stimulated genes through Atf5, which inhibits the transactivation activity of Irf3 known to control IFN-I production. Metabolite analysis demonstrates that Fis1 activation leads to accumulation of fumarate, a TCA cycle intermediate capable of increasing Atf5 activity. Consequently, hepatic Atf5 over-expression or monomethyl fumarate (MMF) treatment improves glucose homeostasis in HFD fed mice. Collectively, these results support the potential use of small molecules targeting the Fis1-Atf5 axis, such as MMF, to treat metabolic diseases.
    Keywords:  Glucose metabolism; Metabolism; Mitochondria; Obesity
    DOI:  https://doi.org/10.1172/jci.insight.150041
  5. iScience. 2022 Jan 21. 25(1): 103650
    Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase.
    Evgeny Shlevkov, Paramasivam Murugan, Dan Montagna, Eric Stefan, Adelajda Hadzipasic, James S Harvey, P Rajesh Kumar, Sonya Entova, Nupur Bansal, Shari Bickford, Lai-Yee Wong, Warren D Hirst, Andreas Weihofen, Laura F Silvian.
      Pharmacological activation of the E3 ligase Parkin represents a rational therapeutic intervention for the treatment of Parkinson's disease. Here we identify several compounds that enhance the activity of wildtype Parkin in the presence of phospho-ubiquitin and act as positive allosteric modulators (PAMs). While these compounds activate Parkin in a series of biochemical assays, they do not act by thermally destabilizing Parkin and fail to enhance the Parkin translocation rate to mitochondria or to enact mitophagy in cell-based assays. We conclude that in the context of the cellular milieu the therapeutic window to pharmacologically activate Parkin is very narrow.
    Keywords:  Biochemistry; Biochemistry Applications; Chemistry
    DOI:  https://doi.org/10.1016/j.isci.2021.103650
  6. EMBO J. 2022 Jan 13. e108587
    DRP1 interacts directly with BAX to induce its activation and apoptosis.
    Andreas Jenner, Aida Peña-Blanco, Raquel Salvador-Gallego, Begoña Ugarte-Uribe, Cristiana Zollo, Tariq Ganief, Jan Bierlmeier, Marcus Mund, Jason E Lee, Jonas Ries, Dirk Schwarzer, Boris Macek, Ana J Garcia-Saez.
      The apoptotic executioner protein BAX and the dynamin-like protein DRP1 co-localize at mitochondria during apoptosis to mediate mitochondrial permeabilization and fragmentation. However, the molecular basis and functional consequences of this interplay remain unknown. Here, we show that BAX and DRP1 physically interact, and that this interaction is enhanced during apoptosis. Complex formation between BAX and DRP1 occurs exclusively in the membrane environment and requires the BAX N-terminal region, but also involves several other BAX surfaces. Furthermore, the association between BAX and DRP1 enhances the membrane activity of both proteins. Forced dimerization of BAX and DRP1 triggers their activation and translocation to mitochondria, where they induce mitochondrial remodeling and permeabilization to cause apoptosis even in the absence of apoptotic triggers. Based on this, we propose that DRP1 can promote apoptosis by acting as noncanonical direct activator of BAX through physical contacts with its N-terminal region.
    Keywords:  BCL-2 proteins; fluorescence correlation spectroscopy; membrane protein complex; mitochondrial division; super-resolution microscopy
    DOI:  https://doi.org/10.15252/embj.2021108587
  7. Cell Rep. 2022 Jan 11. pii: S2211-1247(21)01717-4. [Epub ahead of print]38(2): 110213
    Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes.
    Yoann Combot, Veijo T Salo, Gilliane Chadeuf, Maarit Hölttä, Katharina Ven, Ilari Pulli, Simon Ducheix, Claire Pecqueur, Ophélie Renoult, Behnam Lak, Shiqian Li, Leena Karhinen, Ilya Belevich, Cedric Le May, Jennifer Rieusset, Soazig Le Lay, Mikael Croyal, Karim Si Tayeb, Helena Vihinen, Eija Jokitalo, Kid Törnquist, Corinne Vigouroux, Bertrand Cariou, Jocelyne Magré, Abdelhalim Larhlimi, Elina Ikonen, Xavier Prieur.
      Deficiency of the endoplasmic reticulum (ER) protein seipin results in generalized lipodystrophy by incompletely understood mechanisms. Here, we report mitochondrial abnormalities in seipin-deficient patient cells. A subset of seipin is enriched at ER-mitochondria contact sites (MAMs) in human and mouse cells and localizes in the vicinity of calcium regulators SERCA2, IP3R, and VDAC. Seipin association with MAM calcium regulators is stimulated by fasting-like stimuli, while seipin association with lipid droplets is promoted by lipid loading. Acute seipin removal does not alter ER calcium stores but leads to defective mitochondrial calcium import accompanied by a widespread reduction in Krebs cycle metabolites and ATP levels. In mice, inducible seipin deletion leads to mitochondrial dysfunctions preceding the development of metabolic complications. Together, these data suggest that seipin controls mitochondrial energy metabolism by regulating mitochondrial calcium influx at MAMs. In seipin-deficient adipose tissue, reduced ATP production compromises adipocyte properties, contributing to lipodystrophy pathogenesis.
    Keywords:  ATP production; Adipocyte; Calcium handling; ER-LD contact sites; Krebs cycle metabolites; MAMs; Mitochondria dysfunction; lipid droplet; lipodystrophy; seipin
    DOI:  https://doi.org/10.1016/j.celrep.2021.110213
  8. Nat Commun. 2022 Jan 10. 13(1): 159
    Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer's disease.
    Yun Yang, Victor Tapias, Diana Acosta, Hui Xu, Huanlian Chen, Ruchika Bhawal, Elizabeth T Anderson, Elena Ivanova, Hening Lin, Botir T Sagdullaev, Jianer Chen, William L Klein, Kirsten L Viola, Sam Gandy, Vahram Haroutunian, M Flint Beal, David Eliezer, Sheng Zhang, Gary E Gibson.
      Abnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer's disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aβ accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.
    DOI:  https://doi.org/10.1038/s41467-021-27572-2
  9. iScience. 2022 Jan 21. 25(1): 103722
    SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics.
    Karthik Ramachandran, Soumya Maity, Alagar R Muthukumar, Soundarya Kandala, Dhanendra Tomar, Tarek Mohamed Abd El-Aziz, Cristel Allen, Yuyang Sun, Manigandan Venkatesan, Travis R Madaris, Kevin Chiem, Rachel Truitt, Neelanjan Vishnu, Gregory Aune, Allen Anderson, Luis Martinez, Wenli Yang, James D Stockand, Brij B Singh, Subramanya Srikantan, W Brian Reeves, Muniswamy Madesh.
      SARS-CoV-2 is a newly identified coronavirus that causes the respiratory disease called coronavirus disease 2019 (COVID-19). With an urgent need for therapeutics, we lack a full understanding of the molecular basis of SARS-CoV-2-induced cellular damage and disease progression. Here, we conducted transcriptomic analysis of human PBMCs, identified significant changes in mitochondrial, ion channel, and protein quality-control gene products. SARS-CoV-2 proteins selectively target cellular organelle compartments, including the endoplasmic reticulum and mitochondria. M-protein, NSP6, ORF3A, ORF9C, and ORF10 bind to mitochondrial PTP complex components cyclophilin D, SPG-7, ANT, ATP synthase, and a previously undescribed CCDC58 (coiled-coil domain containing protein 58). Knockdown of CCDC58 or mPTP blocker cyclosporin A pretreatment enhances mitochondrial Ca2+ retention capacity and bioenergetics. SARS-CoV-2 infection exacerbates cardiomyocyte autophagy and promotes cell death that was suppressed by cyclosporin A treatment. Our findings reveal that SARS-CoV-2 viral proteins suppress cardiomyocyte mitochondrial function that disrupts cardiomyocyte Ca2+ cycling and cell viability.
    Keywords:  Cardiovascular medicine; Transcriptomics; Virology
    DOI:  https://doi.org/10.1016/j.isci.2021.103722
  10. Cardiovasc Res. 2022 Jan 09. pii: cvac003. [Epub ahead of print]
    Ulk1-dependent alternative mitophagy plays a protective role during pressure overload in the heart.
    Jihoon Nah, Akihiro Shirakabe, Risa Mukai, Peiyong Zhai, Eun-Ah Sung, Andreas Ivessa, Wataru Mizushima, Yasuki Nakada, Toshiro Saito, Chengchen Hu, Yong-Keun Jung, Junichi Sadoshima.
       AIMS: Well-controlled mitochondrial homeostasis, including a mitochondria-specific form of autophagy (hereafter referred to as mitophagy), is essential for maintaining cardiac function. The molecular mechanism mediating mitophagy during PO is poorly understood. We have shown previously that mitophagy in the heart is mediated primarily by Atg5/Atg7-independent mechanisms, including Unc-51-like kinase1 (Ulk1)-dependent alternative mitophagy, during myocardial ischemia. Here, we investigated the role of alternative mitophagy in the heart during PO-induced hypertrophy.
    METHODS AND RESULTS: Mitophagy was observed in the heart in response to transverse aortic constriction (TAC), peaking at 3-5 days. Whereas mitophagy is transiently upregulated by TAC through an Atg7-dependent mechanism in the heart, peaking at 1 day, it is also activated more strongly and with a delayed time course through an Ulk1-dependent mechanism. TAC induced more severe cardiac dysfunction, hypertrophy and fibrosis in ulk1 cardiac specific knock-out (cKO) mice than in wild type mice. Delayed activation of mitophagy was characterized by the co-localization of Rab9 dots and mitochondria and phosphorylation of Rab9 at Ser179, major features of alternative mitophagy. Furthermore, TAC-induced decreases in the mitochondrial aspect ratio were abolished and the irregularity of mitochondrial cristae was exacerbated, suggesting that mitochondrial quality control mechanisms are impaired in ulk1 cKO mice in response to TAC. TAT-Beclin 1 activates mitophagy even in Ulk1-deficient conditions. TAT-Beclin 1 treatment rescued mitochondrial dysfunction and cardiac dysfunction in ulk1 cKO mice during PO.
    CONCLUSIONS: Ulk1-mediated alternative mitophagy is a major mechanism mediating mitophagy in response to PO and plays an important role in mediating mitochondrial quality control mechanisms and protecting the heart against cardiac dysfunction.
    TRANSLATIONAL PERSPECTIVE: Heart failure is often accompanied by mitochondrial dysfunction in cardiomyocytes. Elimination of dysfunctional mitochondria by mitochondria-specific forms of autophagy, termed mitophagy, is a crucial mechanism for maintaining mitochondrial function in the stressed heart. We discovered that an unconventional form of mitophagy mediated through an Atg7-independent and Ulk1- and Rab9-dependent mechanism is a predominant form of mitophagy in the heart in response to pressure overload. Interventions to restore mitophagy by stimulating the signaling mechanism of the Ulk1-Rab9-dependent mitophagy should delay the development of heart failure in patients with increased afterload.
    Keywords:  Cardiac hypertrophy; Rab9; Ulk1; mitochondria; mitophagy; pressure overload
    DOI:  https://doi.org/10.1093/cvr/cvac003
  11. Autophagy. 2022 Jan 13. 1-2
    Alternative mitophagy is a major form of mitophagy in the chronically stressed heart.
    Junichi Sadoshima.
      Mitochondrial dysfunction is a key determinant of the development of cardiomyopathy in patients with obesity and diabetes. We recently reported that mitophagy is activated in the mouse heart during the chronic phase of high-fat diet (HFD) consumption, despite downregulation of general macroautophagy/autophagy. This form of mitophagy is mediated by a mechanism distinct from that of conventional autophagy and is termed alternative mitophagy. We here discuss the underlying mechanisms of alternative mitophagy and its functional significance in heart disease.
    Keywords:  Mitophagy; Rab9; cardiomyopathy; diabetes; heart; obesity
    DOI:  https://doi.org/10.1080/15548627.2022.2025573
  12. Autophagy. 2022 Jan 09. 1-3
    GAK and PRKCD kinases regulate basal mitophagy.
    Michael J Munson, Benan J Mathai, Matthew Yoke Wui Ng, Laura Trachsel-Moncho, Laura R de la Ballina, Anne Simonsen.
      The removal of mitochondria in a programmed or stress-induced manner is essential for maintaining cellular homeostasis. To date, much research has focused upon stress-induced mitophagy that is largely regulated by the E3 ligase PRKN, with limited insight into the mechanisms regulating basal "housekeeping" mitophagy levels in different model organisms. Using iron chelation as an inducer of PRKN-independent mitophagy, we recently screened an siRNA library of lipid-binding proteins and determined that two kinases, GAK and PRKCD, act as positive regulators of PRKN-independent mitophagy. We demonstrate that PRKCD is localized to mitochondria and regulates recruitment of ULK1-ATG13 upon induction of mitophagy. GAK activity, by contrast, modifies the mitochondrial network and lysosomal morphology that compromise efficient transport of mitochondria for degradation. Impairment of either kinase in vivo blocks basal mitophagy, demonstrating the biological relevance of our findings.Abbreviations: CCCP: carbonyl cyanide-m-chlorophenyl hydrazone; DFP: deferiprone; GAK: cyclin G associated kinase; HIF1A: hypoxia inducible factor 1 subunit alpha; PRKC/PKC: protein kinase C; PRKCD: protein kinase C delta; PRKN: parkin RBR E3 ubiquitin protein ligase.
    Keywords:  Cyclin-G-associated kinase; GAK; PKC; PRKCD; PRKN; mitophagy; protein kinase C
    DOI:  https://doi.org/10.1080/15548627.2021.2015154
  13. Autophagy. 2022 Jan 09. 1-2
    RABEP1/Rabaptin5: a link between autophagy and early endosome homeostasis.
    Valentina Millarte, Martin Spiess.
      Selective autophagy of damaged organelles assures maintenance of cellular homeostasis in eukaryotes. While the mechanisms by which cells selectively remove dysfunctional mitochondria, lysosomes, endoplasmic reticulum and other organelles has been well characterized, little is known about specific autophagy of damaged early endosomes. In our recent study, we uncovered a new role for RABEP1/Rabaptin5, a long-established regulator of early endosome function, in targeting the autophagy machinery to early endosomes damaged by chloroquine or by internalized Salmonella via interaction with RB1CC1/FIP200 and ATG16L1.
    Keywords:  ATG16L1; FIP200; Rabaptin5; Salmonella; autophagy; early endosome
    DOI:  https://doi.org/10.1080/15548627.2021.2021497
  14. Autophagy. 2022 Jan 14. 1-2
    Ceramide-induced mitophagy impairs ß-oxidation-linked energy production in PINK1 deficiency.
    Melissa Vos, Christine Klein.
      Mitophagy and energy production are two functionalities in which PINK1 plays a key role. Loss of PINK1 is one of the genetic causes of Parkinson disease (PD), suggesting both processes are important in PD pathogenesis. Nonetheless, it remains unclear whether these processes are connected or independent of one another. Sphingolipids, including ceramide, have recently emerged as an important new player in the development of PD, however, how alterations in ceramide levels are mechanistically linked to PD remained elusive. In a recently published study, we demonstrated that ceramide accumulates in mitochondria and initiates ceramide-induced mitophagy, thereby compensating for the lack of PINK1-dependent mitophagy upon PINK1 deficiency. However, ceramide accumulation negatively affects ß-oxidation, further aggravating the electron transport chain (ETC) defect caused by PINK1 deficiency and resulting in an additional requirement for mitophagy. Thus, we showed that ceramide serves as a link between the ETC and mitophagy upon PINK1 deficiency. Interruption of this vicious cycle via stimulation of ß-oxidation or reduction of ceramide levels can provide a novel therapeutic target in the treatment of PINK1-related PD.
    Keywords:  PINK1; Parkinson’s disease; ceramide; mitophagy; ß-oxidation
    DOI:  https://doi.org/10.1080/15548627.2022.2027193
  15. Aging Cell. 2022 Jan 13. e13549
    Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia.
    Patricia Gomez-Suaga, Gábor M Mórotz, Andrea Markovinovic, Sandra M Martín-Guerrero, Elisavet Preza, Natalia Arias, Keith Mayl, Afra Aabdien, Vesela Gesheva, Agnes Nishimura, Ambra Annibali, Younbok Lee, Jacqueline C Mitchell, Selina Wray, Christopher Shaw, Wendy Noble, Christopher C J Miller.
      Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER-mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 'tethering' proteins. Here, we show that ER-mitochondria signalling and the VAPB-PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB-PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB-PTPIP51 interaction and ER-mitochondria contacts and that this may involve activation of glycogen synthase kinases-3β (GSK3β), a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca2+ from ER stores to mitochondria, which is a primary function of the VAPB-PTPIP51 tethers. This delivery regulates a number of key neuronal functions that are damaged in ALS/FTD including bioenergetics, autophagy and synaptic function. Our findings reveal a new molecular target for mutant C9orf72-mediated toxicity.
    Keywords:   C9orf72 ; GSK3β; PTPIP51; VAPB; amyotrophic lateral sclerosis; endoplasmic reticulum; frontotemporal dementia; mitochondria
    DOI:  https://doi.org/10.1111/acel.13549
  16. Front Mol Biosci. 2021 ;8 769135
    Absence of Cardiolipin From the Outer Leaflet of a Mitochondrial Inner Membrane Mimic Restricts Opa1-Mediated Fusion.
    Yifan Ge, Sivakumar Boopathy, Tran H Nguyen, Camila Makhlouta Lugo, Luke H Chao.
      Cardiolipin is a tetra-acylated di-phosphatidylglycerol lipid enriched in the matrix-facing (inner) leaflet of the mitochondrial inner membrane. Cardiolipin plays an important role in regulating mitochondria function and dynamics. Yet, the mechanisms connecting cardiolipin distribution and mitochondrial protein function remain indirect. In our previous work, we established an in vitro system reconstituting mitochondrial inner membrane fusion mediated by Opa1. We found that the long form of Opa1 (l-Opa1) works together with the proteolytically processed short form (s-Opa1) to mediate fast and efficient membrane fusion. Here, we extend our reconstitution system to generate supported lipid bilayers with asymmetric cardiolipin distribution. Using this system, we find the presence of cardiolipin on the inter-membrane space-facing (outer) leaflet is important for membrane tethering and fusion. We discuss how the presence of cardiolipin in this leaflet may influence protein and membrane properties, and future applications for this approach.
    Keywords:  OPA1; cardiolipin; membrane asymmetry; membrane heterogeneity; mitochondrial fusion
    DOI:  https://doi.org/10.3389/fmolb.2021.769135
  17. Front Cell Dev Biol. 2021 ;9 803205
    Targeting and Insertion of Membrane Proteins in Mitochondria.
    Ross Eaglesfield, Kostas Tokatlidis.
      Mitochondrial membrane proteins play an essential role in all major mitochondrial functions. The respiratory complexes of the inner membrane are key for the generation of energy. The carrier proteins for the influx/efflux of essential metabolites to/from the matrix. Many other inner membrane proteins play critical roles in the import and processing of nuclear encoded proteins (∼99% of all mitochondrial proteins). The outer membrane provides another lipidic barrier to nuclear-encoded protein translocation and is home to many proteins involved in the import process, maintenance of ionic balance, as well as the assembly of outer membrane components. While many aspects of the import and assembly pathways of mitochondrial membrane proteins have been elucidated, many open questions remain, especially surrounding the assembly of the respiratory complexes where certain highly hydrophobic subunits are encoded by the mitochondrial DNA and synthesised and inserted into the membrane from the matrix side. This review will examine the various assembly pathways for inner and outer mitochondrial membrane proteins while discussing the most recent structural and biochemical data examining the biogenesis process.
    Keywords:  assembly; membrane proteins; mitochondria; mitochondrial chaperones; translocons
    DOI:  https://doi.org/10.3389/fcell.2021.803205
  18. Cells. 2021 Dec 23. pii: 30. [Epub ahead of print]11(1):
    Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis.
    Roberto Iorio, Giuseppe Celenza, Sabrina Petricca.
      Mitochondria are multifunctional subcellular organelles essential for cellular energy homeostasis and apoptotic cell death. It is, therefore, crucial to maintain mitochondrial fitness. Mitophagy, the selective removal of dysfunctional mitochondria by autophagy, is critical for regulating mitochondrial quality control in many physiological processes, including cell development and differentiation. On the other hand, both impaired and excessive mitophagy are involved in the pathogenesis of different ageing-associated diseases such as neurodegeneration, cancer, myocardial injury, liver disease, sarcopenia and diabetes. The best-characterized mitophagy pathway is the PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent pathway. However, other Parkin-independent pathways are also reported to mediate the tethering of mitochondria to the autophagy apparatuses, directly activating mitophagy (mitophagy receptors and other E3 ligases). In addition, the existence of molecular mechanisms other than PINK1-mediated phosphorylation for Parkin activation was proposed. The adenosine5'-monophosphate (AMP)-activated protein kinase (AMPK) is emerging as a key player in mitochondrial metabolism and mitophagy. Beyond its involvement in mitochondrial fission and autophagosomal engulfment, its interplay with the PINK1-Parkin pathway is also reported. Here, we review the recent advances in elucidating the canonical molecular mechanisms and signaling pathways that regulate mitophagy, focusing on the early role and spatial specificity of the AMPK/ULK1 axis.
    Keywords:  AMPK; E3 ligases; PINK1–Parkin pathway; Parkin activation; ULK1; mitochondria; mitophagy; mitophagy receptors; ubiquitin
    DOI:  https://doi.org/10.3390/cells11010030
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