bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒07‒10
thirteen papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression.
  2. Modulating mitofusins to control mitochondrial function and signaling.
  3. Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy.
  4. Sex differences in heart mitochondria regulate diastolic dysfunction.
  5. Mitochondria as Cellular and Organismal Signaling Hubs.
  6. Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation.
  7. Mechanisms of mitochondrial respiratory adaptation.
  8. Overexpression of MRX9 impairs processing of RNAs encoding mitochondrial oxidative phosphorylation factors COB and COX1 in yeast.
  9. Uncovering the source of mitochondrial superoxide in pro-inflammatory macrophages: Insights from immunometabolism.
  10. Alkalization of cellular pH leads to cancer cell death by disrupting autophagy and mitochondrial function.
  11. Autophagy and its mediated mitochondrial quality control maintain pollen tube growth and male fertility in Arabidopsis.
  12. Long read mitochondrial genome sequencing using Cas9-guided adaptor ligation.
  13. Hallmarks and Molecular Tools for the Study of Mitophagy in Parkinson's Disease.
  1. Nat Commun. 2022 Jul 06. 13(1): 3882
    Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression.
    Xinyuan Lei, Hsinyu Lin, Jieqi Wang, Zhanpeng Ou, Yi Ruan, Ananthan Sadagopan, Weixiong Chen, Shule Xie, Baisheng Chen, Qunxing Li, Jue Wang, Huayue Lin, Xiaofeng Zhu, Xiaoqing Yuan, Tian Tian, Xiaobin Lv, Sha Fu, Xiaorui Zhu, Jian Zhou, Guokai Pan, Xin Xia, Bakhos A Tannous, Soldano Ferrone, Song Fan, Jinsong Li.
      Mitochondrial dynamics can regulate Major Histocompatibility Complex (MHC)-I antigen expression by cancer cells and their immunogenicity in mice and in patients with malignancies. A crucial role in the mitochondrial fragmentation connection with immunogenicity is played by the IRE1α-XBP-1s axis. XBP-1s is a transcription factor for aminopeptidase TPP2, which inhibits MHC-I complex cell surface expression likely by degrading tumor antigen peptides. Mitochondrial fission inhibition with Mdivi-1 upregulates MHC-I expression on cancer cells and enhances the efficacy of adoptive T cell therapy in patient-derived tumor models. Therefore mitochondrial fission inhibition might provide an approach to enhance the efficacy of T cell-based immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-022-31417-x
  2. Nat Commun. 2022 Jul 07. 13(1): 3775
    Modulating mitofusins to control mitochondrial function and signaling.
    Emmanouil Zacharioudakis, Bogos Agianian, Vasantha Kumar Mv, Nikolaos Biris, Thomas P Garner, Inna Rabinovich-Nikitin, Amanda T Ouchida, Victoria Margulets, Lars Ulrik Nordstrøm, Joel S Riley, Igor Dolgalev, Yun Chen, Andre J H Wittig, Ryan Pekson, Chris Mathew, Peter Wei, Aristotelis Tsirigos, Stephen W G Tait, Lorrie A Kirshenbaum, Richard N Kitsis, Evripidis Gavathiotis.
      Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins.
    DOI:  https://doi.org/10.1038/s41467-022-31324-1
  3. Nat Commun. 2022 Jul 08. 13(1): 3947
    Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy.
    Xueqiang Wang, Xing Zhang, Ke Cao, Mengqi Zeng, Xuyang Fu, Adi Zheng, Feng Zhang, Feng Gao, Xuan Zou, Hao Li, Min Li, Weiqiang Lv, Jie Xu, Jiangang Long, Weijin Zang, Jinghai Chen, Jian Ding, Jiankang Liu, Zhihui Feng.
      Succinate dehydrogenase, which is known as mitochondrial complex II, has proven to be a fascinating machinery, attracting renewed and increased interest in its involvement in human diseases. Herein, we find that succinate dehydrogenase assembly factor 4 (SDHAF4) is downregulated in cardiac muscle in response to pathological stresses and in diseased hearts from human patients. Cardiac loss of Sdhaf4 suppresses complex II assembly and results in subunit degradation and complex II deficiency in fetal mice. These defects are exacerbated in young adults with globally impaired metabolic capacity and activation of dynamin-related protein 1, which induces excess mitochondrial fission and mitophagy, thereby causing progressive dilated cardiomyopathy and lethal heart failure in animals. Targeting mitochondria via supplementation with fumarate or inhibiting mitochondrial fission improves mitochondrial dynamics, partially restores cardiac function and prolongs the lifespan of mutant mice. Moreover, the addition of fumarate is found to dramatically improve cardiac function in myocardial infarction mice. These findings reveal a vital role for complex II assembly in the development of dilated cardiomyopathy and provide additional insights into therapeutic interventions for heart diseases.
    DOI:  https://doi.org/10.1038/s41467-022-31548-1
  4. Nat Commun. 2022 Jul 04. 13(1): 3850
    Sex differences in heart mitochondria regulate diastolic dysfunction.
    Yang Cao, Laurent Vergnes, Yu-Chen Wang, Calvin Pan, Karthickeyan Chella Krishnan, Timothy M Moore, Manuel Rosa-Garrido, Todd H Kimball, Zhiqiang Zhou, Sarada Charugundla, Christoph D Rau, Marcus M Seldin, Jessica Wang, Yibin Wang, Thomas M Vondriska, Karen Reue, Aldons J Lusis.
      Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial sex differences might underlie this bias. As part of genetic studies of heart failure in mice, we observe that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observe that expression of genes encoding mitochondrial proteins are higher in males than females in human cohorts. We test our hypothesis in a panel of genetically diverse inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, we find that mitochondrial gene expression is highly correlated with diastolic function, a key trait in HFpEF. Consistent with this, studies of a "two-hit" mouse model of HFpEF confirm that mitochondrial function differs between sexes and is strongly associated with a number of HFpEF traits. By integrating data from human heart failure and the mouse HMDP cohort, we identify the mitochondrial gene Acsl6 as a genetic determinant of diastolic function. We validate its role in HFpEF using adenoviral over-expression in the heart. We conclude that sex differences in mitochondrial function underlie, in part, the sex bias in diastolic function.
    DOI:  https://doi.org/10.1038/s41467-022-31544-5
  5. Annu Rev Cell Dev Biol. 2022 Jul 08.
    Mitochondria as Cellular and Organismal Signaling Hubs.
    Koning Shen, Corinne L Pender, Raz Bar-Ziv, Hanlin Zhang, Kevin Wickham, Elizabeth Willey, Jenni Durieux, Qazi Ahmad, Andrew Dillin.
      Mitochondria are traditionally known as the powerhouse of the cell, but their functions extend far beyond energy production. They are vital in cellular and organismal pathways that direct metabolism, stress responses, immunity, and cellular fate. To accomplish these tasks, mitochondria have established networks of both intra- and extracellular communication. Intracellularly, these communication routes comprise direct contacts between mitochondria and other subcellular components as well as indirect vesicle transport of ions, metabolites, and other intracellular messengers. Extracellularly, mitochondria can induce stress responses or other cellular changes that secrete mitochondrial cytokine (mitokine) factors that can travel between tissues as well as respond to immune challenges from extracellular sources. Here we provide a current perspective on the major routes of communication for mitochondrial signaling, including their mechanisms and physiological impact. We also review the major diseases and age-related disorders associated with defects in these signaling pathways. An understanding of how mitochondrial signaling controls cellular homeostasis will bring greater insight into how dysfunctional mitochondria affect health in disease and aging. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 38 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-cellbio-120420-015303
  6. Elife. 2022 Jul 08. pii: e76095. [Epub ahead of print]11
    Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation.
    Simon Stenberg, Jing Li, Arne B Gjuvsland, Karl Persson, Erik Demitz-Helin, Carles González Peña, Jia-Xing Yue, Ciaran Gilchrist, Timmy Ärengård, Payam Ghiaci, Lisa Larsson-Berghund, Martin Zackrisson, Silvana Smits, Johan Hallin, Johanna L Höög, Mikael Molin, Gianni Liti, Stig W Omholt, Jonas Warringer.
      Deletion of mitochondrial DNA in eukaryotes is currently attributed to rare accidental events associated with mitochondrial replication or repair of double-strand breaks. We report the discovery that yeast cells arrest harmful intramitochondrial superoxide production by shutting down respiration through genetically controlled deletion of mitochondrial oxidative phosphorylation genes. We show that this process critically involves the antioxidant enzyme superoxide dismutase 2 and two-way mitochondrial-nuclear communication through Rtg2 and Rtg3. While mitochondrial DNA homeostasis is rapidly restored after cessation of a short-term superoxide stress, long-term stress causes maladaptive persistence of the deletion process, leading to complete annihilation of the cellular pool of intact mitochondrial genomes and irrevocable loss of respiratory ability. This shows that oxidative stress-induced mitochondrial impairment may be under strict regulatory control. If the results extend to human cells, the results may prove to be of etiological as well as therapeutic importance with regard to age-related mitochondrial impairment and disease.
    Keywords:  S. cerevisiae; cell biology; genetics; genomics
    DOI:  https://doi.org/10.7554/eLife.76095
  7. Nat Rev Mol Cell Biol. 2022 Jul 08.
    Mechanisms of mitochondrial respiratory adaptation.
    Christopher F Bennett, Pedro Latorre-Muro, Pere Puigserver.
      Mitochondrial energetic adaptations encompass a plethora of conserved processes that maintain cell and organismal fitness and survival in the changing environment by adjusting the respiratory capacity of mitochondria. These mitochondrial responses are governed by general principles of regulatory biology exemplified by changes in gene expression, protein translation, protein complex formation, transmembrane transport, enzymatic activities and metabolite levels. These changes can promote mitochondrial biogenesis and membrane dynamics that in turn support mitochondrial respiration. The main regulatory components of mitochondrial energetic adaptation include: the transcription coactivator peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC1α) and associated transcription factors; mTOR and endoplasmic reticulum stress signalling; TOM70-dependent mitochondrial protein import; the cristae remodelling factors, including mitochondrial contact site and cristae organizing system (MICOS) and OPA1; lipid remodelling; and the assembly and metabolite-dependent regulation of respiratory complexes. These adaptive molecular and structural mechanisms increase respiration to maintain basic processes specific to cell types and tissues. Failure to execute these regulatory responses causes cell damage and inflammation or senescence, compromising cell survival and the ability to adapt to energetically demanding conditions. Thus, mitochondrial adaptive cellular processes are important for physiological responses, including to nutrient availability, temperature and physical activity, and their failure leads to diseases associated with mitochondrial dysfunction such as metabolic and age-associated diseases and cancer.
    DOI:  https://doi.org/10.1038/s41580-022-00506-6
  8. J Biol Chem. 2022 Jun 29. pii: S0021-9258(22)00656-1. [Epub ahead of print] 102214
    Overexpression of MRX9 impairs processing of RNAs encoding mitochondrial oxidative phosphorylation factors COB and COX1 in yeast.
    Jhulia Almeida Clarck Chagas, Maria Antônia Kfouri Martins Soares, Leticia Veloso Ribeiro Franco, Mário H Barros.
      Mitochondrial translation is a highly regulated process, and newly synthesized mitochondrial products must first associate with several nuclear-encoded auxiliary factors to form oxidative phosphorylation complexes. The output of mitochondrial products should therefore be in stoichiometric equilibrium with the nuclear-encoded products to prevent unnecessary energy expense or the accumulation of pro-oxidant assembly modules. In the mtDNA of Saccharomyces cerevisiae, COX1 encodes subunit 1 of the cytochrome c oxidase, and COB the central core of the cytochrome bc1 electron transfer complex; however, factors regulating the expression of these mitochondrial products are not well described. In this study, we identified Mrx9p as a new factor that controls COX1 and COB expression. We isolated MRX9 in a screen for mitochondrial factors that cause poor accumulation of newly synthesized Cox1p and compromised transition to the respiratory metabolism. Northern analyses indicated lower levels of COX1 and COB mature mRNAs accompanied by an accumulation of unprocessed transcripts in the presence of excess Mrx9p. Furthermore, in a strain devoid of mitochondrial introns, MRX9 overexpression did not affect COX1 and COB translation or respiratory adaptation, implying Mrx9p regulates processing of COX1 and COB RNAs. In addition, we found Mrx9p was localized in the mitochondrial inner membrane, facing the matrix, as a portion of it co-sedimented with mitoribosome subunits and its removal or overexpression altered Mss51p sedimentation. Finally, we showed accumulation of newly synthesized Cox1p in the absence of Mrx9p was diminished in cox14 null mutants. Taken together, these data indicate a regulatory role of Mrx9p in COX1 RNA processing.
    Keywords:  Saccharomyces cerevisiae; intron processing; mitochondrial translation
    DOI:  https://doi.org/10.1016/j.jbc.2022.102214
  9. Biochim Biophys Acta Mol Basis Dis. 2022 Jul 02. pii: S0925-4439(22)00152-1. [Epub ahead of print] 166481
    Uncovering the source of mitochondrial superoxide in pro-inflammatory macrophages: Insights from immunometabolism.
    Alva M Casey, Michael P Murphy.
      Mitochondrial-derived reactive oxygen species are important as antimicrobial agents and redox signals in pro-inflammatory macrophages. Macrophages produce superoxide in response to the TLR4 ligand LPS. However, the mechanism of LPS-induced superoxide generation is not fully understood. Superoxide is produced at complex I and complex III of the electron transport chain. Production of superoxide at either of these sites is highly dependent on the metabolic state of the cell which is dramatically altered by TLR4-induced metabolic reprogramming. This review will outline how metabolism impacts superoxide production in LPS-activated macrophages downstream of TLR4 signalling and address outstanding questions in this field.
    Keywords:  Complex I; Macrophages; Metabolism; Mitochondria; Reverse electron transport; Superoxide
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166481
  10. Oncogene. 2022 Jul 02.
    Alkalization of cellular pH leads to cancer cell death by disrupting autophagy and mitochondrial function.
    Chang Ying, Chengmeng Jin, Siying Zeng, Ming Chao, Xun Hu.
      We previously found that lactic acidosis in the tumor environment was permissive to cancer cell surviving under glucose deprivation and demonstrated that neutralizing lactic acidosis restored cancer cell susceptibility to glucose deprivation. We then reported that alternate infusion of bicarbonate and anticancer agent into tumors via tumor feeding artery markedly enhanced the efficacy of transarterial chemoembolization (TACE) in the local control of hepatocellular carcinoma (HCC). Here we sought to further investigate the mechanism by which bicarbonate enhances the anticancer activity of TACE. We propose that interfering cellular pH by bicarbonate could induce a cascade of molecular events leading to cancer cell death. Alkalizing cellular pH by bicarbonate decreased pH gradient (ΔpH), membrane potential (ΔΨm), and proton motive force (Δp) across the inner membrane of mitochondria; disruption of oxidative phosphorylation (OXPHOS) due to collapsed Δp led to a significant increase in adenosine monophosphate (AMP), which activated the classical AMPK-mediated autophagy. Meanwhile, the autophagic flux was ultimately blocked by increased cellular pH, reduced OXPHOS, and inhibition of lysosomal proton pump in alkalized lysosome. Bicarbonate also induced persistent mitochondrial permeability (MPT) and damaged mitochondria. Collectively, this study reveals that interfering cellular pH may provide a valuable approach to treat cancer.
    DOI:  https://doi.org/10.1038/s41388-022-02396-6
  11. Autophagy. 2022 Jul 04.
    Autophagy and its mediated mitochondrial quality control maintain pollen tube growth and male fertility in Arabidopsis.
    He Yan, Menglong Zhuang, Xiaoyu Xu, Shanshan Li, Mingkang Yang, Nianle Li, Xiaojuan Du, Kangwei Hu, Xiaomin Peng, Wei Huang, Hong Wu, Yu Chung Tse, Lifeng Zhao, Hao Wang.
      Macroautophagy/autophagy, a major catabolic pathway in eukaryotes, participates in plant sexual reproduction including the processes of male gametogenesis and the self-incompatibility response. Rapid pollen tube growth is another essential reproductive process that is metabolically highly demanding to drive the vigorous cell growth for delivery of male gametes for fertilization in angiosperms. Whether and how autophagy operates to maintain the homeostasis of pollen tubes remains unknown. Here, we provide evidence that autophagy is elevated in growing pollen tubes and critically required during pollen tube growth and male fertility in Arabidopsis. We demonstrate that SH3P2, a critical non-ATG regulator of plant autophagy, colocalizes with representative ATG proteins during autophagosome biogenesis in growing pollen tubes. Downregulation of SH3P2 expression significantly disrupts Arabidopsis pollen germination and pollen tube growth. Further analysis of organelle dynamics reveals crosstalk between autophagosomes and prevacuolar compartments following the inhibition of phosphatidylinositol 3-kinase. In addition, time-lapse imaging and tracking of ATG8e-labeled autophagosomes and depolarized mitochondria demonstrate that they interact specifically via the ATG8-family interacting motif (AIM)-docking site to mediate mitophagy. Ultrastructural identification of mitophagosomes and two additional forms of autophagosomes imply that multiple types of autophagy are likely to function simultaneously within pollen tubes. Altogether, our results suggest that autophagy is functionally crucial for mediating mitochondrial quality control and canonical cytoplasm recycling during pollen tube growth.
    Keywords:  ATG8e; Arabidopsis; SH3P2; autophagy; male fertility; mitophagy; pollen tube growth
    DOI:  https://doi.org/10.1080/15548627.2022.2095838
  12. Mitochondrion. 2022 Jul 01. pii: S1567-7249(22)00051-4. [Epub ahead of print]
    Long read mitochondrial genome sequencing using Cas9-guided adaptor ligation.
    Amy R Vandiver, Brittany Pielstick, Timothy Gilpatrick, Austin N Hoang, Hillary J Vernon, Jonathan Wanagat, Winston Timp.
      The mitochondrial genome (mtDNA) is an important source of disease-causing genetic variability, but existing sequencing methods limit understanding, precluding phased measurement of mutations and clear detection of large sporadic deletions. We adapted a method for amplification-free sequence enrichment using Cas9 cleavage to obtain full length nanopore reads of mtDNA. We then utilized the long reads to phase mutations in a patient with an mtDNA-linked syndrome and demonstrated that this method can map age-induced mtDNA deletions. We believe this method will offer deeper insight into our understanding of mtDNA variation.
    Keywords:  Aging; SNPs; Sequencing; mtDNA; mtDNA deletions
    DOI:  https://doi.org/10.1016/j.mito.2022.06.003
  13. Cells. 2022 Jul 02. pii: 2097. [Epub ahead of print]11(13):
    Hallmarks and Molecular Tools for the Study of Mitophagy in Parkinson's Disease.
    Thomas Goiran, Mohamed A Eldeeb, Cornelia E Zorca, Edward A Fon.
      The best-known hallmarks of Parkinson's disease (PD) are the motor deficits that result from the degeneration of dopaminergic neurons in the substantia nigra. Dopaminergic neurons are thought to be particularly susceptible to mitochondrial dysfunction. As such, for their survival, they rely on the elaborate quality control mechanisms that have evolved in mammalian cells to monitor mitochondrial function and eliminate dysfunctional mitochondria. Mitophagy is a specialized type of autophagy that mediates the selective removal of damaged mitochondria from cells, with the net effect of dampening the toxicity arising from these dysfunctional organelles. Despite an increasing understanding of the molecular mechanisms that regulate the removal of damaged mitochondria, the detailed molecular link to PD pathophysiology is still not entirely clear. Herein, we review the fundamental molecular pathways involved in PINK1/Parkin-mediated and receptor-mediated mitophagy, the evidence for the dysfunction of these pathways in PD, and recently-developed state-of-the art assays for measuring mitophagy in vitro and in vivo.
    Keywords:  PINK1; Parkin; Parkinson’s disease; alpha-syn; mito-Keima; mito-QC; mito-SRAI; mitochondrial quality control; mitophagy; protein quality control; ubiquitin
    DOI:  https://doi.org/10.3390/cells11132097
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