bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022–05–01
nineteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Mitochondrial mutations alter endurance exercise response and determinants in mice.
  2. Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis.
  3. Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation.
  4. Macrophage mitochondrial fission improves cancer cell phagocytosis induced by therapeutic antibodies and is impaired by glutamine competition.
  5. Mitochondrial fission in macrophages fuels phagocytosis of tumor cells.
  6. OXPHOS deficiencies affect peroxisome proliferation by downregulating genes controlled by the SNF1 signaling pathway.
  7. CROP: a retromer-PROPPIN complex mediating membrane fission in the endo-lysosomal system.
  8. The endoplasmic reticulum adopts two distinct tubule forms.
  9. Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel.
  10. Rapid manipulation of mitochondrial morphology in a living cell with iCMM.
  11. Measurement of mitochondrial respiratory chain enzymatic activities in Drosophila melanogaster samples.
  12. Methods for mitochondrial health assessment by High Content Imaging System.
  13. Comparative analysis of CI- and CIV-containing respiratory supercomplexes at single-cell resolution.
  14. Essential role of lysosomal Ca2+-mediated TFEB activation in mitophagy and functional adaptation of pancreatic β-cells to metabolic stress.
  15. Mitochondrial hitch-hiking of Pink1 mRNA supports axonal mitophagy.
  16. Mitofusins Mfn1 and Mfn2 are Required to Preserve Glucose- But Not Incretin-Stimulated Beta Cell Connectivity and Insulin Secretion.
  17. Mitochondrial quality control in health and in Parkinson's disease.
  18. The PERKs of mitochondria protection during stress: insights for PERK modulation in neurodegenerative and metabolic diseases.
  19. L-OPA1 deficiency aggravates necroptosis of alveolar epithelial cells through impairing mitochondrial function during ALI in mice.
  1. Proc Natl Acad Sci U S A. 2022 May 03. 119(18): e2200549119
    Mitochondrial mutations alter endurance exercise response and determinants in mice.
    Patrick M Schaefer, Komal Rathi, Arrienne Butic, Wendy Tan, Katherine Mitchell, Douglas C Wallace.
      SignificancePrimary mitochondrial diseases (PMDs) are the most prevalent inborn metabolic disorders, affecting an estimated 1 in 4,200 individuals. Endurance exercise is generally known to improve mitochondrial function, but its indication in the heterogeneous group of PMDs is unclear. We determined the relationship between mitochondrial mutations, endurance exercise response, and the underlying molecular pathways in mice with distinct mitochondrial mutations. This revealed that mitochondria are crucial regulators of exercise capacity and exercise response. Endurance exercise proved to be mostly beneficial across the different mitochondrial mutant mice with the exception of a worsened dilated cardiomyopathy in ANT1-deficient mice. Thus, therapeutic exercises, especially in patients with PMDs, should take into account the physical and mitochondrial genetic status of the patient.
    Keywords:  endurance exercise; mitochondrial disease; skeletal muscle adaption
    DOI:  https://doi.org/10.1073/pnas.2200549119
  2. Nat Commun. 2022 Apr 29. 13(1): 2340
    Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis.
    Vaibhav Sidarala, Jie Zhu, Elena Levi-D'Ancona, Gemma L Pearson, Emma C Reck, Emily M Walker, Brett A Kaufman, Scott A Soleimanpour.
      The dynamin-like GTPases Mitofusin 1 and 2 (Mfn1 and Mfn2) are essential for mitochondrial function, which has been principally attributed to their regulation of fission/fusion dynamics. Here, we report that Mfn1 and 2 are critical for glucose-stimulated insulin secretion (GSIS) primarily through control of mitochondrial DNA (mtDNA) content. Whereas Mfn1 and Mfn2 individually were dispensable for glucose homeostasis, combined Mfn1/2 deletion in β-cells reduced mtDNA content, impaired mitochondrial morphology and networking, and decreased respiratory function, ultimately resulting in severe glucose intolerance. Importantly, gene dosage studies unexpectedly revealed that Mfn1/2 control of glucose homeostasis was dependent on maintenance of mtDNA content, rather than mitochondrial structure. Mfn1/2 maintain mtDNA content by regulating the expression of the crucial mitochondrial transcription factor Tfam, as Tfam overexpression ameliorated the reduction in mtDNA content and GSIS in Mfn1/2-deficient β-cells. Thus, the primary physiologic role of Mfn1 and 2 in β-cells is coupled to the preservation of mtDNA content rather than mitochondrial architecture, and Mfn1 and 2 may be promising targets to overcome mitochondrial dysfunction and restore glucose control in diabetes.
    DOI:  https://doi.org/10.1038/s41467-022-29945-7
  3. Nat Immunol. 2022 Apr 28.
    Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation.
    Leah K Billingham, Joshua S Stoolman, Karthik Vasan, Arianne E Rodriguez, Taylor A Poor, Marten Szibor, Howard T Jacobs, Colleen R Reczek, Aida Rashidi, Peng Zhang, Jason Miska, Navdeep S Chandel.
      The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS). Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.
    DOI:  https://doi.org/10.1038/s41590-022-01185-3
  4. Nat Cancer. 2022 Apr;3(4): 453-470
    Macrophage mitochondrial fission improves cancer cell phagocytosis induced by therapeutic antibodies and is impaired by glutamine competition.
    Jiang Li, Yingying Ye, Zhihan Liu, Guoyang Zhang, Huiqi Dai, Jiaqian Li, Boxuan Zhou, Yihong Li, Qiyi Zhao, Jingying Huang, Jingwei Feng, Shu Liu, Peigang Ruan, Jinjing Wang, Jiang Liu, Min Huang, Xinwei Liu, Shubin Yu, Ziyang Liang, Liping Ma, Xiaoxia Gou, Guoliang Zhang, Nian Chen, Yiwen Lu, Can Di, Qidong Xia, Jiayao Pan, Ru Feng, Qingqing Cai, Shicheng Su.
      Phagocytosis is required for the optimal efficacy of many approved and promising therapeutic antibodies for various malignancies. However, the factors that determine the response to therapies that rely on phagocytosis remain largely elusive. Here, we demonstrate that mitochondrial fission in macrophages induced by multiple antibodies is essential for phagocytosis of live tumor cells. Tumor cells resistant to phagocytosis inhibit mitochondrial fission of macrophages by overexpressing glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which can be targeted to improve antibody efficacy. Mechanistically, increased cytosolic calcium by mitochondrial fission abrogates the phase transition of the Wiskott-Aldrich syndrome protein (WASP)-Wiskott-Aldrich syndrome interacting protein (WIP) complex and enables protein kinase C-θ (PKC-θ) to phosphorylate WIP during phagocytosis. GFPT2-mediated excessive use of glutamine by tumor cells impairs mitochondrial fission and prevents access of PKC-θ to compartmentalized WIP in macrophages. Our data suggest that mitochondrial dynamics dictate the phase transition of the phagocytic machinery and identify GFPT2 as a potential target to improve antibody therapy.
    DOI:  https://doi.org/10.1038/s43018-022-00354-5
  5. Nat Cancer. 2022 Apr;3(4): 384-385
    Mitochondrial fission in macrophages fuels phagocytosis of tumor cells.
      
    DOI:  https://doi.org/10.1038/s43018-022-00350-9
  6. Elife. 2022 Apr 25. pii: e75143. [Epub ahead of print]11
    OXPHOS deficiencies affect peroxisome proliferation by downregulating genes controlled by the SNF1 signaling pathway.
    Jean-Claude Farre, Krypton Carolino, Lou Devanneaux, Suresh Subramani.
      How environmental cues influence peroxisome proliferation, particularly through organelles, remains largely unknown. Yeast peroxisomes metabolize fatty acids (FA), and methylotrophic yeasts also metabolize methanol. NADH and acetyl-CoA, produced by these pathways enter mitochondria for ATP production and for anabolic reactions. During the metabolism of FA and/or methanol, the mitochondrial oxidative phosphorylation (OXPHOS) pathway accepts NADH for ATP production and maintains cellular redox balance. Remarkably, peroxisome proliferation in Pichia pastoris was abolished in NADH shuttling- and OXPHOS mutants affecting complex I or III, or by the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), indicating ATP depletion causes the phenotype. We show that mitochondrial OXPHOS deficiency inhibits expression of several peroxisomal proteins implicated in FA and methanol metabolism, as well as in peroxisome division and proliferation. These genes are regulated by the Snf1 complex (SNF1), a pathway generally activated by a high AMP/ATP ratio. In OXPHOS mutants, Snf1 is activated by phosphorylation, but Gal83, its interacting subunit, fails to translocate to the nucleus. Phenotypic defects in peroxisome proliferation observed in the OXPHOS mutants, and phenocopied by the Dgal83 mutant, were rescued by deletion of three transcriptional repressor genes (MIG1, MIG2 and NRG1) controlled by SNF1 signaling. Our results are interpreted in terms of a mechanism by which peroxisomal and mitochondrial proteins and/or metabolites influence redox and energy metabolism, while also influencing peroxisome biogenesis and proliferation, thereby exemplifying interorganellar communication and interplay involving peroxisomes, mitochondria, cytosol and the nucleus. We discuss the physiological relevance of this work in the context of human OXPHOS deficiencies.
    Keywords:  cell biology
    DOI:  https://doi.org/10.7554/eLife.75143
  7. EMBO J. 2022 Apr 25. e109646
    CROP: a retromer-PROPPIN complex mediating membrane fission in the endo-lysosomal system.
    Thibault Courtellemont, Maria Giovanna De Leo, Navin Gopaldass, Andreas Mayer.
      Endo-lysosomal compartments exchange proteins by fusing, fissioning, and through endosomal transport carriers. Thereby, they sort many plasma membrane receptors and transporters and control cellular signaling and metabolism. How the membrane fission events are catalyzed is poorly understood. Here, we identify the novel CROP complex as a factor acting at this step. CROP joins members of two protein families: the peripheral subunits of retromer, a coat forming endosomal transport carriers, and membrane inserting PROPPINs. Integration into CROP potentiates the membrane fission activity of the PROPPIN Atg18 on synthetic liposomes and confers strong preference for binding PI(3,5)P2 , a phosphoinositide required for membrane fission activity. Disrupting CROP blocks fragmentation of lysosome-like yeast vacuoles in vivo. CROP-deficient mammalian endosomes accumulate micrometer-long tubules and fail to export cargo, suggesting that carriers attempt to form but cannot separate from these organelles. PROPPINs compete for retromer binding with the SNX-BAR proteins, which recruit retromer to the membrane during the formation of endosomal carriers. Transition from retromer-SNX-BAR complexes to retromer-PROPPIN complexes might hence switch retromer activities from cargo capture to membrane fission.
    Keywords:  autophagy; endosomes; lysosomes; retromer; yeast
    DOI:  https://doi.org/10.15252/embj.2021109646
  8. Proc Natl Acad Sci U S A. 2022 May 03. 119(18): e2117559119
    The endoplasmic reticulum adopts two distinct tubule forms.
    Bowen Wang, Zhiheng Zhao, Michael Xiong, Rui Yan, Ke Xu.
      SignificanceThe endoplasmic reticulum (ER) is one of the most structurally visible and functionally important organelles in the cell. Utilizing superresolution microscopy, we here unveil that in the mammalian cell, the peripheral ER adopts two distinct, well-defined tubule forms of contrasting structures, molecular signatures, and functions, with one of the two curiously being ribbon-like, ultranarrow sheets of fixed widths. With fast multicolor microscopy, we further show how the two tubule forms dynamically interconvert while differentially accommodating proteins in the living cell.
    Keywords:  ER tubules; ER-shaping proteins; endoplasmic reticulum; organelle morphology; superresolution microscopy
    DOI:  https://doi.org/10.1073/pnas.2117559119
  9. Nat Chem Biol. 2022 May;18(5): 461-469
    Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel.
    Michael P Murphy, Edward T Chouchani.
      Metabolites once considered solely in catabolism or anabolism turn out to have key regulatory functions. Among these, the citric acid cycle intermediate succinate stands out owing to its multiple roles in disparate pathways, its dramatic concentration changes and its selective cell release. Here we propose that succinate has evolved as a signaling modality because its concentration reflects the coenzyme Q (CoQ) pool redox state, a central redox couple confined to the mitochondrial inner membrane. This connection is of general importance because CoQ redox state integrates three bioenergetic parameters: mitochondrial electron supply, oxygen tension and ATP demand. Succinate, by equilibrating with the CoQ pool, enables the status of this central bioenergetic parameter to be communicated from mitochondria to the rest of the cell, into the circulation and to other cells. The logic of this form of regulation explains many emerging roles of succinate in biology, and suggests future research questions.
    DOI:  https://doi.org/10.1038/s41589-022-01004-8
  10. Cell Rep Methods. 2021 Aug 23. 1(4): 100052
    Rapid manipulation of mitochondrial morphology in a living cell with iCMM.
    Takafumi Miyamoto, Hideki Uosaki, Yuhei Mizunoe, Song-Iee Han, Satoi Goto, Daisuke Yamanaka, Masato Masuda, Yosuke Yoneyama, Hideki Nakamura, Naoko Hattori, Yoshinori Takeuchi, Hiroshi Ohno, Motohiro Sekiya, Takashi Matsuzaka, Fumihiko Hakuno, Shin-Ichiro Takahashi, Naoya Yahagi, Koichi Ito, Hitoshi Shimano.
      Engineered synthetic biomolecular devices that integrate elaborate information processing and precisely regulate living cell behavior have potential in various applications. Although devices that directly regulate key biomolecules constituting inherent biological systems exist, no devices have been developed to control intracellular membrane architecture, contributing to the spatiotemporal functions of these biomolecules. This study developed a synthetic biomolecular device, termed inducible counter mitochondrial morphology (iCMM), to manipulate mitochondrial morphology, an emerging informative property for understanding physiopathological cellular behaviors, on a minute timescale by using a chemically inducible dimerization system. Using iCMM, we determined cellular changes by altering mitochondrial morphology in an unprecedented manner. This approach serves as a platform for developing more sophisticated synthetic biomolecular devices to regulate biological systems by extending manipulation targets from conventional biomolecules to mitochondria. Furthermore, iCMM might serve as a tool for uncovering the biological significance of mitochondrial morphology in various physiopathological cellular processes.
    Keywords:  Boolean logic gate; mitochondria; mitochondrial morphology; synthetic biocomputing device; synthetic biology
    DOI:  https://doi.org/10.1016/j.crmeth.2021.100052
  11. STAR Protoc. 2022 Jun 17. 3(2): 101322
    Measurement of mitochondrial respiratory chain enzymatic activities in Drosophila melanogaster samples.
    Michele Brischigliaro, Elena Frigo, Erika Fernandez-Vizarra, Paolo Bernardi, Carlo Viscomi.
      Mitochondrial respiratory chain (MRC) dysfunction is linked to mitochondrial disease as well as other common conditions such as diabetes, neurodegeneration, cancer, and aging. Thus, the evaluation of MRC enzymatic activities is fundamental for diagnostics and research purposes on experimental models. Here, we provide a verified and reliable protocol for mitochondria isolation from various D. melanogaster samples and subsequent measurement of the activity of MRC complexes I-V plus citrate synthase (CS) through UV-VIS spectrophotometry. For complete details on the use and execution of this protocol, please refer to Brischigliaro et al. (2021).
    Keywords:  Cell separation/fractionation; Metabolism; Model Organisms; Protein Biochemistry
    DOI:  https://doi.org/10.1016/j.xpro.2022.101322
  12. MethodsX. 2022 ;9 101685
    Methods for mitochondrial health assessment by High Content Imaging System.
    Chatnapa Panusatid, Nattachai Thangsiriskul, Chayanon Peerapittayamongkol.
      Mitochondria are important organelles responsible for energy production. Mitochondrial dysfunction relates to various pathological diseases. The investigation of mitochondrial heath is critical to evaluate the cellular status. Herein, we demonstrated an approach for determining the status of mitochondrial health by observing mitochondrial H2O2 (one type of ROS), membrane potential, and morphology (fragmentation and length) in live primary fibroblast cells. The cells were co-stained with fluorescent dyes (Hoechst 33342 and MITO-ID® Red/MitoPY1/JC-10) and continuously processed by the High Content Imaging System. We employed the Operetta CLSTM to take fluorescent images with its given quickness and high resolution. The CellProfiler image analysis software was further used to identify cell and mitochondrial phenotypes in the thousand fluorescent images.•We could quantitatively analyze fluorescent images with high-throughput and high-speed detection to track the alteration of mitochondrial status.•The MMP assay is sensitive to FCCP even at the concentration of 0.01 µM.•The fibroblast cells treated with stress inducers (H2O2, FCCP, and phenanthroline) revealed a significant change in mitochondrial health parameters, with more ROS accumulation, depolarized MMP, increased fragmentation, and reduced length of mitochondria.
    Keywords:  High content fluorescent imaging; Mitochondrial ROS; Mitochondrial function; Mitochondrial membrane potential; Mitochondrial morphology
    DOI:  https://doi.org/10.1016/j.mex.2022.101685
  13. Cell Rep Methods. 2021 May 24. 1(1): 100002
    Comparative analysis of CI- and CIV-containing respiratory supercomplexes at single-cell resolution.
    Fabio Bertan, Lena Wischhof, Enzo Scifo, Mihaela Guranda, Joshua Jackson, Anaïs Marsal-Cots, Antonia Piazzesi, Miriam Stork, Michael Peitz, Jochen Herbert Martin Prehn, Dan Ehninger, Pierluigi Nicotera, Daniele Bano.
      Mitochondria sustain the energy demand of the cell. The composition and functional state of the mitochondrial oxidative phosphorylation system are informative indicators of organelle bioenergetic capacity. Here, we describe a highly sensitive and reproducible method for a single-cell quantification of mitochondrial CI- and CIV-containing respiratory supercomplexes (CI∗CIV-SCs) as an alternative means of assessing mitochondrial respiratory chain integrity. We apply a proximity ligation assay (PLA) and stain CI∗CIV-SCs in fixed human and mouse brains, tumorigenic cells, induced pluripotent stem cells (iPSCs) and iPSC-derived neural precursor cells (NPCs), and neurons. Spatial visualization of CI∗CIV-SCs enables the detection of mitochondrial lesions in various experimental models, including complex tissues undergoing degenerative processes. We report that comparative assessments of CI∗CIV-SCs facilitate the quantitative profiling of even subtle mitochondrial variations by overcoming the confounding effects that mixed cell populations have on other measurements. Together, our PLA-based analysis of CI∗CIV-SCs is a sensitive and complementary technique for detecting cell-type-specific mitochondrial perturbations in fixed materials.
    Keywords:  brain; in-situ imaging analysis; mitochondria; mitochondrial diseases; mitochondrial dysfunction; mitochondrial respiratory supercomplexes; proximity ligation assay
    DOI:  https://doi.org/10.1016/j.crmeth.2021.100002
  14. Autophagy. 2022 Apr 25.
    Essential role of lysosomal Ca2+-mediated TFEB activation in mitophagy and functional adaptation of pancreatic β-cells to metabolic stress.
    Kihyoun Park, Myung-Shik Lee.
      Although the role of pancreatic β-cell macroautophagy/autophagy is well known, that of β-cell mitophagy is unclear. We investigated the changes of lysosomal Ca2+ by mitochondrial or metabolic stress that can modulate TFEB activation and, additionally, the role of TFEB-induced mitophagy in β-cell function. Mitochondrial or metabolic stress induces mitophagy, which is mediated by lysosomal Ca2+ release, increased cytosolic [Ca2+] and subsequent TFEB activation. Lysosomal Ca2+ release is replenished by ER→lysosome Ca2+ refilling through ER Ca2+ exit channels, which is important for the increase of cytosolic [Ca2+] and mitophagy by mitochondria stressors. High-fat diet (HFD) feeding augments pancreatic β-cell mitophagy, probably as an adaptation to metabolic stress. HFD-induced increase of β-cell mitophagy is reduced by tfeb KO, leading to increased ROS and decreased mitochondrial complex activity or oxygen consumption in tfeb-KO islets. In tfeb Δβ-cell mice, HFD-induced glucose intolerance and β-cell dysfunction are aggravated. Expression of mitophagy receptor genes including Optn or Calcoco2 is increased by mitochondrial or metabolic stressors in a TFEB-dependent manner, likely contributing to increased mitophagy. These results suggest that lysosomal Ca2+ release in conjunction with ER→lysosome Ca2+ refilling is important for TFEB activation and mitophagy induction, which contributes to pancreatic β-cell adaptation to metabolic stress.
    Keywords:  Ca2+; TFEB; lysosome; mitophagy; pancreatic β-cells
    DOI:  https://doi.org/10.1080/15548627.2022.2069956
  15. Autophagy. 2022 Apr 26.
    Mitochondrial hitch-hiking of Pink1 mRNA supports axonal mitophagy.
    Angelika B Harbauer, Thomas L Schwarz.
      Mitostasis, the process of mitochondrial maintenance by biogenesis and degradative mechanisms, is challenged by the extreme length of axons. PINK1 (PTEN induced putative kinase 1) is a mitochondrial protein that targets damaged mitochondria for mitophagy. In reconciling the short half-life of PINK1 with the need for mitophagy of damaged axonal mitochondria, we found that axonal mitophagy depends on local translation of the Pink1 mRNA. Using live-cell imaging, we detected co-transport of the Pink1 mRNA on mitochondria in neurons, which is crucial for mitophagy in distal parts of the cell. Here we discuss how the coupling of the transcript of a short-lived mitochondrial protein to the movement of its target organelles contributes to our understanding of mitostasis in neurons.
    Keywords:  Axonal biology; RNA transport; local translation; mitochondria; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2070332
  16. Diabetes. 2022 Apr 26. pii: db210800. [Epub ahead of print]
    Mitofusins Mfn1 and Mfn2 are Required to Preserve Glucose- But Not Incretin-Stimulated Beta Cell Connectivity and Insulin Secretion.
    Eleni Georgiadou, Charanya Muralidharan, Michelle Martinez, Pauline Chabosseau, Elina Akalestou, Alejandra Tomas, Fiona Yong Su Wern, Theodoros Stylianides, Asger Wretlind, Cristina Legido-Quigley, Ben Jones, Livia Lopez Noriega, Yanwen Xu, Guoqiang Gu, Nour Alsabeeh, Céline Cruciani-Guglielmacci, Christophe Magnan, Mark Ibberson, Isabelle Leclerc, Yusuf Ali, Scott A Soleimanpour, Amelia K Linnemann, Tristan A Rodriguez, Guy A Rutter.
      Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic beta cells. Whether mitofusin gene expression, and hence mitochondrial network integrity, is important for glucose or incretin signalling has not previously been explored. Here, we generated mice with beta cell-selective, adult-restricted deletion of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). βMfn1/2 dKO mice displayed elevated fed and fasted glycaemia and a >five-fold decrease in plasma insulin. Mitochondrial length, glucose-induced polarisation, ATP synthesis, cytosolic and mitochondrial Ca2+ increases were all reduced in dKO islets. In contrast, oral glucose tolerance was more modestly affected in βMfn1/2 dKO mice and GLP-1 or GIP receptor agonists largely corrected defective GSIS through enhanced EPAC-dependent signalling. Correspondingly, cAMP increases in the cytosol, as measured with an Epac-camps based sensor, were exaggerated in dKO mice. Mitochondrial fusion and fission cycles are thus essential in the beta cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in beta cells, the potential contributions of altered mitochondrial dynamics to diabetes development and the impact of incretins on this process.
    DOI:  https://doi.org/10.2337/db21-0800
  17. Physiol Rev. 2022 Apr 25.
    Mitochondrial quality control in health and in Parkinson's disease.
    Mohamed A Eldeeb, Rhalena A Thomas, Mohamed A Ragheb, Armaan Fallahi, Edward A Fon.
      As a central hub for cellular metabolism and intracellular signalling, the mitochondrion is a pivotal organelle, dysfunction of which has been linked to several human diseases including neurodegenerative disorders, and in particular Parkinson's disease. An inherent challenge that mitochondria face is the continuous exposure to diverse stresses which increase their likelihood of dysregulation. In response, eukaryotic cells have evolved sophisticated quality control mechanisms to monitor, identify, repair and/or eliminate abnormal or misfolded proteins within the mitochondrion and/or the dysfunctional mitochondrion itself. Chaperones identify unstable or otherwise abnormal conformations in mitochondrial proteins and can promote their refolding to recover their correct conformation and stability. However, if repair is not possible, the abnormal protein is selectively degraded to prevent potentially damaging interactions with other proteins or its oligomerization into toxic multimeric complexes. The autophagic-lysosomal system and the ubiquitin-proteasome system mediate the selective and targeted degradation of such abnormal or misfolded protein species. Mitophagy (a specific kind of autophagy) mediates the selective elimination of dysfunctional mitochondria, in order to prevent the deleterious effects the dysfunctional organelles within the cell. Despite our increasing understanding of the molecular responses toward dysfunctional mitochondria, many key aspects remain relatively poorly understood. Herein, we review the emerging mechanisms of mitochondrial quality control including quality control strategies coupled to mitochondrial import mechanisms. In addition, we review the molecular mechanisms regulating mitophagy with an emphasis on the regulation of PINK1/PARKIN-mediated mitophagy in cellular physiology and in the context of Parkinson's disease cell biology.
    Keywords:  PINK1/Parkin; Parkinson's disease; mitochondrial quality control; mitophagy; protein quality control
    DOI:  https://doi.org/10.1152/physrev.00041.2021
  18. Biol Rev Camb Philos Soc. 2022 Apr 26.
    The PERKs of mitochondria protection during stress: insights for PERK modulation in neurodegenerative and metabolic diseases.
    Liliana M Almeida, Brígida R Pinho, Michael R Duchen, Jorge M A Oliveira.
      Protein kinase RNA-like ER kinase (PERK) is an endoplasmic reticulum (ER) stress sensor that responds to the accumulation of misfolded proteins. Once activated, PERK initiates signalling pathways that halt general protein production, increase the efficiency of ER quality control, and maintain redox homeostasis. PERK activation also protects mitochondrial homeostasis during stress. The location of PERK at the contact sites between the ER and the mitochondria creates a PERK-mitochondria axis that allows PERK to detect stress in both organelles, adapt their functions and prevent apoptosis. During ER stress, PERK activation triggers mitochondrial hyperfusion, preventing premature apoptotic fragmentation of the mitochondria. PERK activation also increases the formation of mitochondrial cristae and the assembly of respiratory supercomplexes, enhancing cellular ATP-generating capacity. PERK strengthens mitochondrial quality control during stress by promoting the expression of mitochondrial chaperones and proteases and by increasing mitochondrial biogenesis and mitophagy, resulting in renewal of the mitochondrial network. But how does PERK mediate all these changes in mitochondrial homeostasis? In addition to the classic PERK-eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4) pathway, PERK can activate other protective pathways - PERK-O-linked N-acetyl-glucosamine transferase (OGT), PERK-transcription factor EB (TFEB), and PERK-nuclear factor erythroid 2-related factor 2 (NRF2) - contributing to broader regulation of mitochondrial dynamics, metabolism, and quality control. The pharmacological activation of PERK is protective in models of neurodegenerative and metabolic diseases, such as Huntington's disease, progressive supranuclear palsy and obesity, while the inhibition of PERK was protective in models of Parkinson's and prion diseases and diabetes. In this review, we address the molecular mechanisms by which PERK regulates mitochondrial dynamics, metabolism and quality control, and discuss the therapeutic potential of targeting PERK in neurodegenerative and metabolic diseases.
    Keywords:  PERK; dynamics; endoplasmic reticulum; metabolic diseases; metabolism; mitochondria; neurodegeneration; stress; unfolded protein response
    DOI:  https://doi.org/10.1111/brv.12860
  19. J Cell Physiol. 2022 Apr 28.
    L-OPA1 deficiency aggravates necroptosis of alveolar epithelial cells through impairing mitochondrial function during ALI in mice.
    Hui-Ling Jiang, Hui-Hui Yang, Yu-Biao Liu, Chen-Yu Zhang, Wen-Jing Zhong, Xin-Xin Guan, Ling Jin, Jie-Ru Hong, Jin-Tong Yang, Xiao-Hua Tan, Qing Li, Yong Zhou, Cha-Xiang Guan.
      Necroptosis, a recently described form of programmed cell death, is the main way of alveolar epithelial cells (AECs) death in acute lung injury (ALI). While the mechanism of how to trigger necroptosis in AECs during ALI has been rarely evaluated. Long optic atrophy protein 1 (L-OPA1) is a crucial mitochondrial inner membrane fusion protein, and its deficiency impairs mitochondrial function. This study aimed to investigate the role of L-OPA1 deficiency-mediated mitochondrial dysfunction in AECs necroptosis. We comprehensively investigated the detailed contribution and molecular mechanism of L-OPA1 deficiency in AECs necroptosis by inhibiting or activating L-OPA1. Firstly, our data showed that L-OPA1 expression was down-regulated in the lungs and AECs under the lipopolysaccharide (LPS) challenge. Furthermore, inhibition of L-OPA1 aggravated the pathological injury, inflammatory response, and necroptosis in the lungs of LPS-induced ALI mice. In vitro, inhibition of L-OPA1 induced necroptosis of AECs, while activation of L-OPA1 alleviated necroptosis of AECs under the LPS challenge. Mechanistically, inhibition of L-OPA1 aggravated necroptosis of AECs by inducing mitochondrial fragmentation and reducing mitochondrial membrane potential. While activation of L-OPA1 had the opposite effects. In summary, these findings indicate for the first time that L-OPA1 deficiency mediates mitochondrial fragmentation, induces necroptosis of AECs, and exacerbates ALI in mice. This article is protected by copyright. All rights reserved.
    Keywords:  L-OPA1; acute lung injury; alveolar epithelial cells; mitochondrial fragmentation; necroptosis
    DOI:  https://doi.org/10.1002/jcp.30766
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