bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2023–08–06
eight papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial quality control in hepatic ischemia-reperfusion injury.
  2. Contact sites between endoplasmic reticulum sheets and mitochondria regulate mitochondrial DNA replication and segregation.
  3. FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo.
  4. Completion of mitochondrial division requires the intermembrane space protein Mdi1/Atg44.
  5. Nanoscale details of mitochondrial constriction revealed by cryo-electron tomography.
  6. Convergent and divergent mechanisms of peroxisomal and mitochondrial division.
  7. FAM210A regulates mitochondrial translation and maintains cardiac mitochondrial homeostasis.
  8. Mitochondrial quality control in lung diseases: current research and future directions.
  1. Heliyon. 2023 Jul;9(7): e17702
    Mitochondrial quality control in hepatic ischemia-reperfusion injury.
    LiuSong Wang, Zan Jie Feng, Xuan Ma, Kai Li, Xin Yao Li, Yi Tang, Cijun Peng.
      Hepatic ischemia-reperfusion injury is a phenomenon in which exacerbating damage of liver cells due to restoration of blood flow following ischemia during liver surgery, especially those involving liver transplantation. Mitochondria, the energy-producing organelles, are crucial for cell survival and apoptosis and have evolved a range of quality control mechanisms to maintain homeostasis in the mitochondrial network in response to various stress conditions. Hepatic ischemia-reperfusion leads to disruption of mitochondrial quality control mechanisms, as evidenced by reduced mitochondrial autophagy, excessive division, reduced fusion, and inhibition of biogenesis. This leads to dysfunction of the mitochondrial network. The accumulation of damaged mitochondria ultimately results in apoptosis of hepatocytes due to the release of apoptotic proteins like cytochrome C. This worsens hepatic ischemia-reperfusion injury. Currently, hepatic ischemia-reperfusion injury protection is being studied using different approaches such as drug pretreatment, stem cells and exosomes, genetic interventions, and mechanical reperfusion, all aimed at targeting mitochondrial quality control mechanisms. This paper aims to provide direction for future research on combating HIRI by reviewing the latest studies that focus on targeting mitochondrial quality control mechanisms.
    Keywords:  Hepatic ischemia-reperfusion injury; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control mechanisms; Mitophagy
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e17702
  2. iScience. 2023 Jul 21. 26(7): 107180
    Contact sites between endoplasmic reticulum sheets and mitochondria regulate mitochondrial DNA replication and segregation.
    Hema Saranya Ilamathi, Sara Benhammouda, Amel Lounas, Khalid Al-Naemi, Justine Desrochers-Goyette, Matthew A Lines, François J Richard, Jackie Vogel, Marc Germain.
      Mitochondria are multifaceted organelles crucial for cellular homeostasis that contain their own genome. Mitochondrial DNA (mtDNA) replication is a spatially regulated process essential for the maintenance of mitochondrial function, its defect causing mitochondrial diseases. mtDNA replication occurs at endoplasmic reticulum (ER)-mitochondria contact sites and is affected by mitochondrial dynamics: The absence of mitochondrial fusion is associated with mtDNA depletion whereas loss of mitochondrial fission causes the aggregation of mtDNA within abnormal structures termed mitobulbs. Here, we show that contact sites between mitochondria and ER sheets, the ER structure associated with protein synthesis, regulate mtDNA replication and distribution within mitochondrial networks. DRP1 loss or mutation leads to modified ER sheets and alters the interaction between ER sheets and mitochondria, disrupting RRBP1-SYNJ2BP interaction. Importantly, mtDNA distribution and replication were rescued by promoting ER sheets-mitochondria contact sites. Our work identifies the role of ER sheet-mitochondria contact sites in regulating mtDNA replication and distribution.
    Keywords:  Biochemistry; Biological sciences; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107180
  3. PLoS Biol. 2023 Aug 03. 21(8): e3002244
    FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo.
    Alvaro Sanchez-Martinez, Aitor Martinez, Alexander J Whitworth.
      Functional analyses of genes linked to heritable forms of Parkinson's disease (PD) have revealed fundamental insights into the biological processes underpinning pathogenic mechanisms. Mutations in PARK15/FBXO7 cause autosomal recessive PD and FBXO7 has been shown to regulate mitochondrial homeostasis. We investigated the extent to which FBXO7 and its Drosophila orthologue, ntc, share functional homology and explored its role in mitophagy in vivo. We show that ntc mutants partially phenocopy Pink1 and parkin mutants and ntc overexpression supresses parkin phenotypes. Furthermore, ntc can modulate basal mitophagy in a Pink1- and parkin-independent manner by promoting the ubiquitination of mitochondrial proteins, a mechanism that is opposed by the deubiquitinase USP30. This basal ubiquitination serves as the substrate for Pink1-mediated phosphorylation that triggers stress-induced mitophagy. We propose that FBXO7/ntc works in equilibrium with USP30 to provide a checkpoint for mitochondrial quality control in basal conditions in vivo and presents a new avenue for therapeutic approaches.
    DOI:  https://doi.org/10.1371/journal.pbio.3002244
  4. J Cell Biol. 2023 Oct 02. pii: e202303147. [Epub ahead of print]222(10):
    Completion of mitochondrial division requires the intermembrane space protein Mdi1/Atg44.
    Olivia M Connor, Srujan K Matta, Jonathan R Friedman.
      Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by a dynamin-related protein, Dnm1 (Drp1 in humans), that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity is sufficient to complete the fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1 (also named Atg44). Loss of Mdi1 causes mitochondrial hyperfusion due to defects in fission, but not the lack of Dnm1 recruitment to mitochondria. Mdi1 is conserved in fungal species, and its homologs contain an amphipathic α-helix, mutations of which disrupt mitochondrial morphology. One model is that Mdi1 distorts mitochondrial membranes to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of Mdi1 inside mitochondria.
    DOI:  https://doi.org/10.1083/jcb.202303147
  5. Biophys J. 2023 Aug 01. pii: S0006-3495(23)00481-2. [Epub ahead of print]
    Nanoscale details of mitochondrial constriction revealed by cryo-electron tomography.
    Shrawan Kumar Mageswaran, Danielle Ann Grotjahn, Xiangrui Zeng, Benjamin Asher Barad, Michaela Medina, My Hanh Hoang, Megan J Dobro, Yi-Wei Chang, Min Xu, Wei Yuan Yang, Grant J Jensen.
      Mitochondria adapt to changing cellular environments, stress stimuli, and metabolic demands through dramatic morphological remodeling of their shape, and thus function. Such mitochondrial dynamics is often dependent on cytoskeletal filament interactions. However, the precise organization of these filamentous assemblies remains speculative. Here, we apply cryogenic electron tomography to directly image the nanoscale architecture of the cytoskeletal-membrane interactions involved in mitochondrial dynamics in response to damage. We induced mitochondrial damage via membrane depolarization, a cellular stress associated with mitochondrial fragmentation and mitophagy. We find that, in response to acute membrane depolarization, mammalian mitochondria predominantly organize into tubular morphology that abundantly displays constrictions. We observe long bundles of both unbranched actin and septin filaments enriched at these constrictions. We also observed septin-microtubule interactions at these sites and elsewhere suggesting that these two filaments guide each other in the cytosolic space. Together, our results provide empirical parameters for the architecture of mitochondrial constriction factors to validate/refine existing models and inform the development of new ones.
    DOI:  https://doi.org/10.1016/j.bpj.2023.07.030
  6. J Cell Biol. 2023 09 04. pii: e202304076. [Epub ahead of print]222(9):
    Convergent and divergent mechanisms of peroxisomal and mitochondrial division.
    Suresh Subramani, Nandini Shukla, Jean-Claude Farre.
      Organelle division and segregation are important in cellular homeostasis. Peroxisomes (POs) and mitochondria share a core division machinery and mechanism of membrane scission. The division of each organelle is interdependent not only on the other but also on other organelles, reflecting the dynamic communication between subcellular compartments, even as they coordinate the exchange of metabolites and signals. We highlight common and unique mechanisms involved in the fission of these organelles under the premise that much can be gleaned regarding the division of one organelle based on information available for the other.
    DOI:  https://doi.org/10.1083/jcb.202304076
  7. Cardiovasc Res. 2023 Jul 31. pii: cvad124. [Epub ahead of print]
    FAM210A regulates mitochondrial translation and maintains cardiac mitochondrial homeostasis.
    Jiangbin Wu, Kadiam C Venkata Subbaiah, Omar Hedaya, Si Chen, Joshua Munger, Wai Hong Wilson Tang, Chen Yan, Peng Yao.
       AIMS: Mitochondria play a vital role in cellular metabolism and energetics and support normal cardiac function. Disrupted mitochondrial function and homeostasis cause a variety of heart diseases. Fam210a (family with sequence similarity 210 member A), a novel mitochondrial gene, is identified as a hub gene in mouse cardiac remodeling by multi-omics studies. Human FAM210A mutations are associated with sarcopenia. However, the physiological role and molecular function of FAM210A remain elusive in the heart. We aim to determine the biological role and molecular mechanism of FAM210A in regulating mitochondrial function and cardiac health in vivo.
    METHODS AND RESULTS: Tamoxifen-induced αMHCMCM-driven conditional knockout of Fam210a in the mouse cardiomyocytes induced progressive dilated cardiomyopathy and heart failure, ultimately causing mortality. Fam210a deficient cardiomyocytes exhibit severe mitochondrial morphological disruption and functional decline accompanied by myofilament disarray at the late stage of cardiomyopathy. Furthermore, we observed increased mitochondrial reactive oxygen species production, disturbed mitochondrial membrane potential, and reduced respiratory activity in cardiomyocytes at the early stage before contractile dysfunction and heart failure. Multi-omics analyses indicate that FAM210A deficiency persistently activates integrated stress response (ISR), resulting in transcriptomic, translatomic, proteomic, and metabolomic reprogramming, ultimately leading to pathogenic progression of heart failure. Mechanistically, mitochondrial polysome profiling analysis shows that FAM210A loss of function compromises mitochondrial mRNA translation and leads to reduced mitochondrial encoded proteins, followed by disrupted proteostasis. We observed decreased FAM210A protein expression in human ischemic heart failure and mouse myocardial infarction tissue samples. To further corroborate FAM210A function in the heart, AAV9-mediated overexpression of FAM210A promotes mitochondrial-encoded protein expression, improves cardiac mitochondrial function, and partially rescues murine hearts from cardiac remodeling and damage in ischemia-induced heart failure.
    CONCLUSION: These results suggest that FAM210A is a mitochondrial translation regulator to maintain mitochondrial homeostasis and normal cardiomyocyte contractile function. This study also offers a new therapeutic target for treating ischemic heart disease.
    Keywords:  FAM210A; cardiomyopathy; heart failure; integrated stress response; mRNA translation; metabolism; mitochondria; myocardial infarction
    DOI:  https://doi.org/10.1093/cvr/cvad124
  8. Front Physiol. 2023 ;14 1236651
    Mitochondrial quality control in lung diseases: current research and future directions.
    Jiliu Liu, Junyi Wang, Anying Xiong, Lei Zhang, Yi Zhang, Yao Liu, Ying Xiong, Guoping Li, Xiang He.
      Lung diseases are a major global health problem, affecting millions of people worldwide. Recent research has highlighted the critical role that mitochondrial quality control plays in respiratory-related diseases, including chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF). In this review, we summarize recent findings on the involvement of mitochondrial quality control in these diseases and discuss potential therapeutic strategies. Mitochondria are essential organelles for energy production and other cellular processes, and their dysfunction is associated with various diseases. The quality control of mitochondria involves a complex system of pathways, including mitophagy, mitochondrial biogenesis, fusion/fission dynamics, and regulation of gene expression. In COPD and lung cancer, mitochondrial quality control is often involved in disease development by influencing oxidative stress and apoptosis. In IPF, it appears to be involved in the disease process by participating in the cellular senescence process. Mitochondrial quality control is a promising target for therapeutic interventions in lung diseases. However, there are conflicting reports on different pathological processes, such as the role of mitochondrial autophagy in lung cancer, which pose difficulties in the study of targeted mitochondrial quality control drugs. Additionally, there seems to be a delicate balance between the mitochondrial quality control processes in the physiological state. Emerging evidence suggests that molecules such as PTEN-induced putative kinase 1 (PINK1), parkin RBR E3 ubiquitin protein ligase (PRKN), dynamin-related protein 1 (DRP1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), as well as the signaling pathways they affect, play an important role in respiratory-related diseases. Targeting these molecules and pathways could contribute to the development of effective treatments for lung diseases. In conclusion, the involvement of mitochondrial quality control in lung diseases presents a promising new avenue for disease treatment. Further research is needed to better understand the complex mechanisms involved in the pathogenesis of respiratory diseases and to develop targeted therapies that could improve clinical outcomes.
    Keywords:  chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; lung cancer; mitochondrial quality control; therapeutic approaches
    DOI:  https://doi.org/10.3389/fphys.2023.1236651
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