bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022–06–19
eight papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy.
  2. Dynamic rearrangement and autophagic degradation of mitochondria during spermiogenesis in the liverwort Marchantia polymorpha.
  3. CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.
  4. CG7630 is the Drosophila melanogaster homolog of the cytochrome c oxidase subunit COX7B.
  5. FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion.
  6. A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells.
  7. Structure of the second phospho-ubiquitin binding site in parkin.
  8. Mitofusin 2 positively regulates Ca2+ signaling by tethering the sarcoplasmic reticulum and mitochondria in rat aortic smooth muscle cells.
  1. J Clin Invest. 2022 Jun 14. pii: e157504. [Epub ahead of print]
    OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy.
    Mario K Shammas, Xiaoping Huang, Beverly P Wu, Evelyn Fessler, Insung Song, Nicholas P Randolph, Yan Li, Christopher Ke Bleck, Danielle A Springer, Carl Fratter, Ines A Barbosa, Andrew F Powers, Pedro M Quirós, Carlos Lopez-Otin, Lucas T Jae, Joanna Poulton, Derek P Narendra.
      Mitochondrial stress triggers a response in the cell's mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we characterize a family with myopathy caused by a dominant p.G58R mutation in the mitochondrial protein CHCHD10. To understand the disease etiology, we developed a knock-in mouse model and found that mutant CHCHD10 aggregates in affected tissues, applying a toxic protein stress to the inner mitochondrial membrane. Unexpectedly, survival of CHCHD10 knock-in mice depended on a protective stress response mediated by OMA1. The OMA1 stress response acted both locally within mitochondria, causing mitochondrial fragmentation, and signaled outside the mitochondria, activating the integrated stress response through cleavage of DELE1. We additionally identified an isoform switch in the terminal complex of the electron transport chain as a component of this response. Our results demonstrate that OMA1 is critical for neonatal survival conditionally in the setting of inner mitochondrial membrane stress, coordinating local and global stress responses to reshape the mitochondrial network and proteome.
    Keywords:  Cell Biology; Cell stress; Genetics; Mitochondria; Proteases
    DOI:  https://doi.org/10.1172/JCI157504
  2. Cell Rep. 2022 Jun 14. pii: S2211-1247(22)00761-6. [Epub ahead of print]39(11): 110975
    Dynamic rearrangement and autophagic degradation of mitochondria during spermiogenesis in the liverwort Marchantia polymorpha.
    Takuya Norizuki, Naoki Minamino, Miyuki Sato, Hirokazu Tsukaya, Takashi Ueda.
      Mitochondria change their morphology in response to developmental and environmental cues. During sexual reproduction, bryophytes produce spermatozoids with two mitochondria in the cell body. Although intensive morphological analyses have been conducted, how this fixed number of mitochondria is realized remains poorly understood. Here, we investigate how mitochondria are reorganized during spermiogenesis in Marchantia polymorpha. We find that the mitochondrial number is reduced to one through fission followed by autophagic degradation during early spermiogenesis, and then the posterior mitochondrion arises by fission of the anterior mitochondrion. Autophagy is also responsible for the removal of other organelles, including peroxisomes, but these other organelles are removed at distinct developmental stages from mitochondrial degradation. We also find that spermiogenesis involves nonautophagic organelle degradation. Our findings highlight the dynamic reorganization of mitochondria, which is regulated distinctly from that of other organelles, and multiple degradation mechanisms operate in organelle remodeling during spermiogenesis in M. polymorpha.
    Keywords:  CP: Plants; Marchantia polymorpha; autophagy; dynamin-related protein; mitochondria; mitochondrial fission; mitophagy; nonautophagic degradation; organelle reorganization; peroxisome; spermiogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2022.110975
  3. Sci Adv. 2022 Jun 17. 8(24): eabo4271
    CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.
    Ping-Min Chen, Eri Katsuyama, Abhigyan Satyam, Hao Li, Jose Rubio, Sungwook Jung, Sylvia Andrzejewski, J David Becherer, Maria G Tsokos, Reza Abdi, George C Tsokos.
      Infection is one of the major causes of mortality in patients with systemic lupus erythematosus (SLE). We previously found that CD38, an ectoenzyme that regulates the production of NAD+, is up-regulated in CD8+ T cells of SLE patients and correlates with the risk of infection. Here, we report that CD38 reduces CD8+ T cell function by negatively affecting mitochondrial fitness through the inhibition of multiple steps of mitophagy, a process that is critical for mitochondria quality control. Using a murine lupus model, we found that administration of a CD38 inhibitor in a CD8+ T cell-targeted manner reinvigorated their effector function, reversed the defects in autophagy and mitochondria, and improved viral clearance. We conclude that CD38 represents a target to mitigate infection rates in people with SLE.
    DOI:  https://doi.org/10.1126/sciadv.abo4271
  4. EMBO Rep. 2022 Jun 14. e54825
    CG7630 is the Drosophila melanogaster homolog of the cytochrome c oxidase subunit COX7B.
    Michele Brischigliaro, Alfredo Cabrera-Orefice, Mattia Sturlese, Dei M Elurbe, Elena Frigo, Erika Fernandez-Vizarra, Stefano Moro, Martijn A Huynen, Susanne Arnold, Carlo Viscomi, Massimo Zeviani.
      The mitochondrial respiratory chain (MRC) is composed of four multiheteromeric enzyme complexes. According to the endosymbiotic origin of mitochondria, eukaryotic MRC derives from ancestral proteobacterial respiratory structures consisting of a minimal set of complexes formed by a few subunits associated with redox prosthetic groups. These enzymes, which are the "core" redox centers of respiration, acquired additional subunits, and increased their complexity throughout evolution. Cytochrome c oxidase (COX), the terminal component of MRC, has a highly interspecific heterogeneous composition. Mammalian COX consists of 14 different polypeptides, of which COX7B is considered the evolutionarily youngest subunit. We applied proteomic, biochemical, and genetic approaches to investigate the COX composition in the invertebrate model Drosophila melanogaster. We identified and characterized a novel subunit which is widely different in amino acid sequence, but similar in secondary and tertiary structures to COX7B, and provided evidence that this object is in fact replacing the latter subunit in virtually all protostome invertebrates. These results demonstrate that although individual structures may differ the composition of COX is functionally conserved between vertebrate and invertebrate species.
    Keywords:   D. melanogaster ; COX7B; cytochrome c oxidase; mitochondria; respiratory chain
    DOI:  https://doi.org/10.15252/embr.202254825
  5. Nat Commun. 2022 Jun 17. 13(1): 3486
    FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion.
    Shuaifeng Li, Shixun Han, Qi Zhang, Yibing Zhu, Haitao Zhang, Junli Wang, Yang Zhao, Jianhui Zhao, Lin Su, Li Li, Dawang Zhou, Cunqi Ye, Xin-Hua Feng, Tingbo Liang, Bin Zhao.
      Mitochondria generate ATP and play regulatory roles in various cellular activities. Cancer cells often exhibit fragmented mitochondria. However, the underlying mechanism remains elusive. Here we report that a mitochondrial protein FUN14 domain containing 2 (FUNDC2) is transcriptionally upregulated in primary mouse liver tumors, and in approximately 40% of human hepatocellular carcinoma (HCC). Importantly, elevated FUNDC2 expression inversely correlates with patient survival, and its knockdown inhibits liver tumorigenesis in mice. Mechanistically, the amino-terminal region of FUNDC2 interacts with the GTPase domain of mitofusin 1 (MFN1), thus inhibits its activity in promoting fusion of outer mitochondrial membrane. As a result, loss of FUNDC2 leads to mitochondrial elongation, decreased mitochondrial respiration, and reprogrammed cellular metabolism. These results identified a mechanism of mitochondrial fragmentation in cancer through MFN1 inhibition by FUNDC2, and suggested FUNDC2 as a potential therapeutic target of HCC.
    DOI:  https://doi.org/10.1038/s41467-022-31187-6
  6. J Cell Biol. 2022 Jul 04. pii: e202109144. [Epub ahead of print]221(7):
    A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells.
    Brian G Coon, Sushma Timalsina, Matteo Astone, Zhen W Zhuang, Jennifer Fang, Jinah Han, Jurgen Themen, Minhwan Chung, Young Joo Yang-Klingler, Mukesh Jain, Karen K Hirschi, Ai Yamamato, Louis-Eric Trudeau, Massimo Santoro, Martin A Schwartz.
      Atherosclerosis, the major cause of myocardial infarction and stroke, results from converging inflammatory, metabolic, and biomechanical factors. Arterial lesions form at sites of low and disturbed blood flow but are suppressed by high laminar shear stress (LSS) mainly via transcriptional induction of the anti-inflammatory transcription factor, Kruppel-like factor 2 (Klf2). We therefore performed a whole genome CRISPR-Cas9 screen to identify genes required for LSS induction of Klf2. Subsequent mechanistic investigation revealed that LSS induces Klf2 via activation of both a MEKK2/3-MEK5-ERK5 kinase module and mitochondrial metabolism. Mitochondrial calcium and ROS signaling regulate assembly of a mitophagy- and p62-dependent scaffolding complex that amplifies MEKK-MEK5-ERK5 signaling. Blocking the mitochondrial pathway in vivo reduces expression of KLF2-dependent genes such as eNOS and inhibits vascular remodeling. Failure to activate the mitochondrial pathway limits Klf2 expression in regions of disturbed flow. This work thus defines a connection between metabolism and vascular inflammation that provides a new framework for understanding and developing treatments for vascular disease.
    DOI:  https://doi.org/10.1083/jcb.202109144
  7. J Biol Chem. 2022 Jun 08. pii: S0021-9258(22)00555-5. [Epub ahead of print] 102114
    Structure of the second phospho-ubiquitin binding site in parkin.
    Rayan Fakih, Véronique Sauvé, Kalle Gehring.
      Parkin and PINK1 regulate a mitochondrial quality control system that is mutated in some early onset forms of Parkinson's disease. Parkin is an E3 ubiquitin ligase and regulated by the mitochondrial kinase PINK1 via a two-step cascade. PINK1 first phosphorylates ubiquitin, which binds a recruitment site on parkin to localize parkin to damaged mitochondria. In the second step, PINK1 phosphorylates parkin on its ubiquitin-like domain (Ubl) domain, which binds a regulatory site to release ubiquitin ligase activity. Recently, an alternative feed-forward mechanism was identified that bypasses the need for parkin phosphorylation through the binding of a second phospho-ubiquitin (pUb) molecule. Here, we report the structure of parkin activated through this feed-forward mechanism. The crystal structure of parkin with pUb bound to both the recruitment and regulatory sites reveals the molecular basis for differences in specificity and affinity of the two sites. We use isothermal titration calorimetry measurements to reveal cooperativity between the two binding sites and the role of linker residues for pUbl binding to the regulatory site. The observation of flexibility in the process of parkin activation offers hope for the future design of small molecules for the treatment of Parkinson's disease.
    DOI:  https://doi.org/10.1016/j.jbc.2022.102114
  8. Am J Physiol Cell Physiol. 2022 Jun 15.
    Mitofusin 2 positively regulates Ca2+ signaling by tethering the sarcoplasmic reticulum and mitochondria in rat aortic smooth muscle cells.
    Sou Inagaki, Yoshiaki Suzuki, Keisuke Kawasaki, Rubii Kondo, Yuji Imaizumi, Hisao Yamamura.
      Mitochondria buffer cytosolic Ca2+increases following Ca2+ influx from extracellular spaces and Ca2+ release from intracellular Ca2+ store sites under physiological circumstances. Therefore, close contact of mitochondria with the sarcoplasmic reticulum (SR) is required for maintaining Ca2+ homeostasis. Mitofusin 2 (Mfn2) localizes in both mitochondrial and SR membranes, and is hypothesized to optimize the distance and Ca2+ transfer between these organelles. However, the physiological significance of Mfn2 in vascular smooth muscle cells (VSMCs) is poorly understood. In the present study, the role of Mfn2 in the physical and functional couplings between SR and mitochondria was examined in rat aortic smooth muscle cells (rASMCs) by confocal and electron microscope imaging. When Mfn2 was knocked-down using siRNA in rASMCs, the mean distance between these organelles was extended from 16.2 to 21.6 nm. The increase in the cytosolic Ca2+ concentration ([Ca2+]cyt) induced by 100 nM arginine vasopressin (AVP) was not affected by Mfn2 siRNA knockdown, whereas cytosolic Ca2+ removal was slower after Mfn2 knockdown. Following the AVP-induced [Ca2+]cyt increase, mitochondrial Ca2+ uptake and Ca2+ refill into the SR were attenuated by Mfn2 knockdown. In addition, Mfn2-knockdown cells exhibited a loss of mitochondrial membrane potential (ΔΨmito) and lower ATP levels in mitochondria. Moreover, Mfn2 knockdown inhibited cell proliferation. In contrast, Mfn2 overexpression increased ΔΨmito and cell growth. This study strongly suggests that Mfn2 is responsible for SR-mitochondria Ca2+ signaling by tethering mitochondria to SR, thereby regulating ATP production and proliferation of VSMCs.
    Keywords:  calcium; mitochondria; mitofusin; sarcoplasmic reticulum; smooth muscle
    DOI:  https://doi.org/10.1152/ajpcell.00274.2021
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:23.