bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒09‒18
twelve papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. A universal coupling mechanism of respiratory complex I.
  2. mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity.
  3. Mitochondria transfer mediates stress erythropoiesis by altering the bioenergetic profiles of early erythroblasts through CD47.
  4. OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy.
  5. Cryptococcal Hsf3 controls intramitochondrial ROS homeostasis by regulating the respiratory process.
  6. The emergent role of mitochondrial surveillance in cellular health.
  7. Calcium homeostasis in the control of mitophagy.
  8. ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response.
  9. ER exit sites (ERES) and ER-mitochondria encounter structures (ERMES) often localize proximally.
  10. Mitochondrial dysfunction triggers actin polymerization necessary for rapid glycolytic activation.
  11. Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1α and the NAMPT-NAD+ pathway.
  12. TRIM27 is an autophagy substrate facilitating mitochondria clustering and mitophagy via phosphorylated TBK1.
  1. Nature. 2022 Sep 14.
    A universal coupling mechanism of respiratory complex I.
    Vladyslav Kravchuk, Olga Petrova, Domen Kampjut, Anna Wojciechowska-Bason, Zara Breese, Leonid Sazanov.
      Complex I is the first enzyme in the respiratory chain, which is responsible for energy production in mitochondria and bacteria1. Complex I couples the transfer of two electrons from NADH to quinone and the translocation of four protons across the membrane2, but the coupling mechanism remains contentious. Here we present cryo-electron microscopy structures of Escherichia coli complex I (EcCI) in different redox states, including catalytic turnover. EcCI exists mostly in the open state, in which the quinone cavity is exposed to the cytosol, allowing access for water molecules, which enable quinone movements. Unlike the mammalian paralogues3, EcCI can convert to the closed state only during turnover, showing that closed and open states are genuine turnover intermediates. The open-to-closed transition results in the tightly engulfed quinone cavity being connected to the central axis of the membrane arm, a source of substrate protons. Consistently, the proportion of the closed state increases with increasing pH. We propose a detailed but straightforward and robust mechanism comprising a 'domino effect' series of proton transfers and electrostatic interactions: the forward wave ('dominoes stacking') primes the pump, and the reverse wave ('dominoes falling') results in the ejection of all pumped protons from the distal subunit NuoL. This mechanism explains why protons exit exclusively from the NuoL subunit and is supported by our mutagenesis data. We contend that this is a universal coupling mechanism of complex I and related enzymes.
    DOI:  https://doi.org/10.1038/s41586-022-05199-7
  2. Cell. 2022 Sep 08. pii: S0092-8674(22)01112-6. [Epub ahead of print]
    mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity.
    Antonio J Pagán, Lauren J Lee, Joy Edwards-Hicks, Cecilia B Moens, David M Tobin, Elisabeth M Busch-Nentwich, Erika L Pearce, Lalita Ramakrishnan.
      Necrosis of macrophages in the granuloma, the hallmark immunological structure of tuberculosis, is a major pathogenic event that increases host susceptibility. Through a zebrafish forward genetic screen, we identified the mTOR kinase, a master regulator of metabolism, as an early host resistance factor in tuberculosis. We found that mTOR complex 1 protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis. These metabolic adaptations are required to prevent mitochondrial damage and death caused by the secreted mycobacterial virulence determinant ESAT-6. Thus, the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism, thereby allowing pathogen-specific immune mechanisms time to develop. Our findings may explain why Mycobacterium tuberculosis, albeit humanity's most lethal pathogen, is successful in only a minority of infected individuals.
    Keywords:  ESAT-6 mitotoxicity; Mycobacterium marinum; Mycobacterium tuberculosis; granuloma necrosis; mTOR; macrophage death; mitochondrial metabolism; oxidative phosphorylation; tuberculosis; zebrafish TB model
    DOI:  https://doi.org/10.1016/j.cell.2022.08.018
  3. J Exp Med. 2022 Dec 05. pii: e20220685. [Epub ahead of print]219(12):
    Mitochondria transfer mediates stress erythropoiesis by altering the bioenergetic profiles of early erythroblasts through CD47.
    Chong Yang, Rui Yokomori, Lee Hui Chua, Shi Hao Tan, Darren Qiancheng Tan, Kenichi Miharada, Takaomi Sanda, Toshio Suda.
      Intercellular mitochondria transfer is a biological phenomenon implicated in diverse biological processes. However, the physiological role of this phenomenon remains understudied between erythroblasts and their erythroblastic island (EBI) macrophage niche. To gain further insights into the mitochondria transfer functions, we infused EBI macrophages in vivo into mice subjected to different modes of anemic stresses. Interestingly, we observed the occurrence of mitochondria transfer events from the infused EBI macrophages to early stages of erythroblasts coupled with enhanced erythroid recovery. Single-cell RNA-sequencing analysis on erythroblasts receiving exogenous mitochondria revealed a subset of highly proliferative and metabolically active erythroid populations marked by high expression of CD47. Furthermore, CD47 or Sirpα blockade leads to a decline in both the occurrence of mitochondria transfer events and their mediated erythroid recovery. Hence, these data indicate a significant role of mitochondria transfer in the enhancement of erythroid recovery from stress through the alteration of the bioenergetic profiles via CD47-Sirpα interaction in the early stages of erythroblasts.
    DOI:  https://doi.org/10.1084/jem.20220685
  4. Cell Metab. 2022 Sep 08. pii: S1550-4131(22)00360-6. [Epub ahead of print]
    OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy.
    Sofia Ahola, Pablo Rivera Mejías, Steffen Hermans, Srikanth Chandragiri, Patrick Giavalisco, Hendrik Nolte, Thomas Langer.
      Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by deficiencies in the oxidative phosphorylation (OXPHOS) system of mitochondria. Here, we demonstrate that the cardiac-specific loss of the assembly factor Cox10 of the cytochrome c oxidase causes mitochondrial cardiomyopathy in mice, which is associated with OXPHOS deficiency, lysosomal defects, and an aberrant mitochondrial morphology. Activation of the mitochondrial peptidase Oma1 in Cox10-/- mice results in mitochondrial fragmentation and induction of the integrated stress response (ISR) along the Oma1-Dele1-Atf4 signaling axis. Ablation of Oma1 or Dele1 in Cox10-/- mice aggravates cardiomyopathy. ISR inhibition impairs the cardiac glutathione metabolism, limits the selenium-dependent accumulation of the glutathione peroxidase Gpx4, and increases lipid peroxidation in the heart, ultimately culminating in ferroptosis. Our results demonstrate a protective role of the Oma1-Dele1-mediated ISR in mitochondrial cardiomyopathy and link ferroptosis to OXPHOS deficiency and mitochondrial disease.
    Keywords:  Atf4; Dele1; Gpx4; Oma1; cardiomyopathy; ferroptosis; glutathione; integrated stress response; mitochondria; selenium
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.017
  5. Nat Commun. 2022 Sep 15. 13(1): 5407
    Cryptococcal Hsf3 controls intramitochondrial ROS homeostasis by regulating the respiratory process.
    Xindi Gao, Yi Fu, Shengyi Sun, Tingyi Gu, Yanjian Li, Tianshu Sun, Hailong Li, Wei Du, Chenhao Suo, Chao Li, Yiru Gao, Yang Meng, Yue Ni, Sheng Yang, Tian Lan, Sixiang Sai, Jiayi Li, Kun Yu, Ping Wang, Chen Ding.
      Mitochondrial quality control prevents accumulation of intramitochondrial-derived reactive oxygen species (mtROS), thereby protecting cells against DNA damage, genome instability, and programmed cell death. However, underlying mechanisms are incompletely understood, particularly in fungal species. Here, we show that Cryptococcus neoformans heat shock factor 3 (CnHsf3) exhibits an atypical function in regulating mtROS independent of the unfolded protein response. CnHsf3 acts in nuclei and mitochondria, and nuclear- and mitochondrial-targeting signals are required for its organelle-specific functions. It represses the expression of genes involved in the tricarboxylic acid cycle while promoting expression of genes involved in electron transfer chain. In addition, CnHsf3 responds to multiple intramitochondrial stresses; this response is mediated by oxidation of the cysteine residue on its DNA binding domain, which enhances DNA binding. Our results reveal a function of HSF proteins in regulating mtROS homeostasis that is independent of the unfolded protein response.
    DOI:  https://doi.org/10.1038/s41467-022-33168-1
  6. Aging Cell. 2022 Sep 11. e13710
    The emergent role of mitochondrial surveillance in cellular health.
    Elissa Tjahjono, Daniel R Kirienko, Natalia V Kirienko.
      Mitochondrial dysfunction is one of the primary causatives for many pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and aging. Decline in mitochondrial functions leads to the loss of proteostasis, accumulation of ROS, and mitochondrial DNA damage, which further exacerbates mitochondrial deterioration in a vicious cycle. Surveillance mechanisms, in which mitochondrial functions are closely monitored for any sign of perturbations, exist to anticipate possible havoc within these multifunctional organelles with primitive origin. Various indicators of unhealthy mitochondria, including halted protein import, dissipated membrane potential, and increased loads of oxidative damage, are on the top of the lists for close monitoring. Recent research also indicates a possibility of reductive stress being monitored as part of a mitochondrial surveillance program. Upon detection of mitochondrial stress, multiple mitochondrial stress-responsive pathways are activated to promote the transcription of numerous nuclear genes to ameliorate mitochondrial damage and restore compromised cellular functions. Co-expression occurs through functionalization of transcription factors, allowing their binding to promoter elements to initiate transcription of target genes. This review provides a comprehensive summary of the intricacy of mitochondrial surveillance programs and highlights their roles in our cellular life. Ultimately, a better understanding of these surveillance mechanisms is expected to improve healthspan.
    Keywords:  aging; mitochondria; mitochondrial membrane transport proteins; mitophagy; physiological stress; reactive oxygen species; surveillance
    DOI:  https://doi.org/10.1111/acel.13710
  7. Antioxid Redox Signal. 2022 Sep 16.
    Calcium homeostasis in the control of mitophagy.
    Mariasole Perrone, Simone Patergnani, Tommaso Di Mambro, Laura Palumbo, Mariusz Więckowski, Carlotta Giorgi, Paolo Pinton.
      SIGNIFICANCE: Maintenance of mitochondrial quality is essential for cellular homeostasis. Among processes responsible for preserving healthy mitochondria, mitophagy selectively eliminates dysfunctional mitochondria by targeting them to the autophagosome for degradation. Alterations in mitophagy lead to the accumulation of damaged mitochondria, which plays an essential role in several diseases like carcinogenesis and tumor progression, neurodegenerative disorders, and autoimmune and cardiovascular pathologies.RECENT ADVANCES: Calcium (Ca2+) plays a fundamental role in cell life, modulating several pathways, such as gene expression, proliferation, differentiation, metabolism, cell death, and survival. Indeed, because it is involved in all these events, Ca2+ is the most versatile intracellular second messenger. Being a process that limits cellular degeneration, mitophagy participates in cellular fate decisions. Several mitochondrial parameters, such as membrane potential, structure, and reactive oxygen species, can trigger the activation of mitophagic machinery. These parameters regulate not only mitophagy but also the mitochondrial Ca2+ uptake.
    CRITICAL ISSUES: Ca2+ handling is fundamental in regulating ATP production by mitochondria and mitochondrial quality control processes. Despite the growing literature about the link between Ca2+ and mitophagy, the mechanism by which Ca2+ homeostasis regulates mitophagy is still debated.
    FUTURE DIRECTIONS: Several studies have revealed that excessive mitophagy together with altered mitochondrial Ca2+ uptake leads to different dysfunctions in numerous diseases. Thus, therapeutic modulation of these pathways is considered promising treatments.
    DOI:  https://doi.org/10.1089/ars.2022.0122
  8. J Lipid Res. 2022 Sep 10. pii: S0022-2275(22)00112-2. [Epub ahead of print] 100279
    ER Stress-Induced Sphingosine-1-Phosphate Lyase Phosphorylation Potentiates the Mitochondrial Unfolded Protein Response.
    Asli D Yildirim, Mevlut Citir, Asli E Dogan, Zehra Veli, Zehra Yildirim, Ozlem Tufanli, Alexis Traynor Kaplan, Carsten Schultz, Ebru Erbay.
      The unfolded protein response (UPR) is an elaborate signaling network that evolved to maintain proteostasis in the endoplasmic reticulum (ER) and mitochondria (mt). These organelles are functionally and physically associated and consequently, their stress responses are often intertwined. It is unclear how these two adaptive stress responses are coordinated during ER stress. The inositol-requiring enzyme-1 (IRE1), a central ER stress sensor and proximal regulator of the UPRER, harbors dual kinase and endoribonuclease (RNase) activities. IRE1 RNase activity initiates the transcriptional layer of the UPRER, but IRE1's kinase substrate(s) and their functions are largely unknown. Here, we discovered that sphingosine 1-phosphate (S1P) lyase (SPL), the enzyme that degrades S1P, is a substrate for the mammalian IRE1 kinase. Our data show that IRE1-dependent SPL phosphorylation inhibits SPL's enzymatic activity, resulting in increased intracellular S1P levels. S1P has previously been shown to induce the activation of mitochondrial UPR (UPRmt) in nematodes. We determined that IRE1 kinase-dependent S1P induction during ER stress potentiates UPRmt signaling in mammalian cells. Phosphorylation of eukaryotic translation initiation factor 2α (eif2α) is recognized as a critical molecular event for UPRmt activation in mammalian cells. Our data further demonstrate that inhibition of the IRE1-SPL axis abrogates the activation of two eif2α kinases, namely double-stranded RNA-activated protein kinase (PKR) and PKR-like ER kinase (PERK) upon ER stress. These findings show that the IRE1-SPL axis plays a central role in coordinating the adaptive responses of both organelles to ER stress in mammalian cells.
    Keywords:  Adaptive Stress Response; Endoplasmic Reticulum; Endoribonuclease; Eukaryotic Translation Initiation Factor 2α; IRE1-SPL axis; Inositol-Requiring Enzyme-1; Kinase; Mitochondria; Proteostasis; Signaling Networks
    DOI:  https://doi.org/10.1016/j.jlr.2022.100279
  9. FEBS Lett. 2022 Sep 14.
    ER exit sites (ERES) and ER-mitochondria encounter structures (ERMES) often localize proximally.
    Naini Chakraborty, Bhawik Kumar Jain, Samruddhi Shembekar, Dibyendu Bhattacharyya.
      To understand the potential interplay between vesicular trafficking and direct membrane contact sites mediated transport, we selected the endoplasmic reticulum (ER), which participates in both modes of inter-organelle transport. ER-mitochondria encounter structures (ERMES) are direct membrane contact junctions that mediate macromolecule exchange, while the secretory pathway originates at ER exit sites (ERES). Using the budding yeast Pichia pastoris, we documented that ERMES resident proteins are often juxtaposed with ERES markers. We further demonstrated that ERES form de novo almost always near a pre-existing ERMES. Disruption of either ERES or ERMES affects the other. Djp1, a chaperone reported to mediate mitochondrial import of ER-resident proteins, localizes at the ERES-ERMES proximal region. Our results indicate a potential functional link between ERES-ERMES proximity and mitochondrial protein import.
    DOI:  https://doi.org/10.1002/1873-3468.14497
  10. J Cell Biol. 2022 Nov 07. pii: e202201160. [Epub ahead of print]221(11):
    Mitochondrial dysfunction triggers actin polymerization necessary for rapid glycolytic activation.
    Rajarshi Chakrabarti, Tak Shun Fung, Taewook Kang, Pieti W Elonkirjo, Anu Suomalainen, Edward J Usherwood, Henry N Higgs.
      Mitochondrial damage represents a dramatic change in cellular homeostasis. One rapid response is perimitochondrial actin polymerization, termed acute damage-induced actin (ADA). The consequences of ADA are not understood. In this study, we show evidence suggesting that ADA is linked to rapid glycolytic activation upon mitochondrial damage in multiple cells, including mouse embryonic fibroblasts and effector CD8+ T lymphocytes. ADA-inducing treatments include CCCP, antimycin, rotenone, oligomycin, and hypoxia. The Arp2/3 complex inhibitor CK666 or the mitochondrial sodium-calcium exchanger (NCLX) inhibitor CGP37157 inhibits both ADA and the glycolytic increase within 5 min, supporting ADA's role in glycolytic stimulation. Two situations causing chronic reductions in mitochondrial ATP production, mitochondrial DNA depletion and mutation to the NDUFS4 subunit of complex 1 of the electron transport chain, cause persistent perimitochondrial actin filaments similar to ADA. CK666 treatment causes rapid mitochondrial actin loss and a drop in ATP in NDUFS4 knock-out cells. We propose that ADA is necessary for rapid glycolytic activation upon mitochondrial impairment, to re-establish ATP production.
    DOI:  https://doi.org/10.1083/jcb.202201160
  11. Nucleic Acids Res. 2022 Sep 13. pii: gkac741. [Epub ahead of print]
    Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1α and the NAMPT-NAD+ pathway.
    Scott Maynard, Arnaldur Hall, Panagiotis Galanos, Salvatore Rizza, Tatsuro Yamamoto, Helena Hagner Gram, Sebastian H N Munk, Muhammad Shoaib, Claus Storgaard Sørensen, Vilhelm A Bohr, Mads Lerdrup, Apolinar Maya-Mendoza, Jiri Bartek.
      Mutations in the lamin A/C gene (LMNA) cause laminopathies such as the premature aging Hutchinson Gilford progeria syndrome (HGPS) and altered lamin A/C levels are found in diverse malignancies. The underlying lamin-associated mechanisms remain poorly understood. Here we report that lamin A/C-null mouse embryo fibroblasts (Lmna-/- MEFs) and human progerin-expressing HGPS fibroblasts both display reduced NAD+ levels, unstable mitochondrial DNA and attenuated bioenergetics. This mitochondrial dysfunction is associated with reduced chromatin recruitment (Lmna-/- MEFs) or low levels (HGPS) of PGC1α, the key transcription factor for mitochondrial homeostasis. Lmna-/- MEFs showed reduced expression of the NAD+-biosynthesis enzyme NAMPT and attenuated activity of the NAD+-dependent deacetylase SIRT1. We find high PARylation in lamin A/C-aberrant cells, further decreasing the NAD+ pool and consistent with impaired DNA base excision repair in both cell models, a condition that fuels DNA damage-induced PARylation under oxidative stress. Further, ATAC-sequencing revealed a substantially altered chromatin landscape in Lmna-/- MEFs, including aberrantly reduced accessibility at the Nampt gene promoter. Thus, we identified a new role of lamin A/C as a key modulator of mitochondrial function through impairments of PGC1α and the NAMPT-NAD+ pathway, with broader implications for the aging process.
    DOI:  https://doi.org/10.1093/nar/gkac741
  12. FEBS J. 2022 Sep 16.
    TRIM27 is an autophagy substrate facilitating mitochondria clustering and mitophagy via phosphorylated TBK1.
    Juncal Garcia-Garcia, Anne Kristin McLaren Berge, Katrine Stange Overå, Kenneth Bowitz Larsen, Zambarlal Bhujabal, Andreas Brech, Yakubu Princely Abudu, Trond Lamark, Terje Johansen, Eva Sjøttem.
      Tripartite motif containing protein 27 (TRIM27/also called RFP) is a multifunctional ubiquitin E3 ligase involved in numerous cellular functions, such as proliferation, apoptosis, regulation of the NF-kB pathway, endosomal recycling, and the innate immune response. TRIM27 interacts directly with TANK-binding kinase 1 (TBK1) and regulates its stability. TBK1 in complex with autophagy receptors are recruited to ubiquitin chains assembled on the mitochondrial outer membrane promoting mitophagy. Here we identify TRIM27 as an autophagy substrate, depending on ATG7, ATG9 and autophagy receptors for its lysosomal degradation. We show that TRIM27 forms ubiquitylated cytoplasmic bodies that colocalize with autophagy receptors. Surprisingly, we observed that induced expression of EGFP-TRIM27 in HEK293 FlpIn TRIM27 Knock-Out cells mediates mitochondrial clustering. TRIM27 interacts with autophagy receptor SQSTM1/p62, and the TRIM27 mediated mitochondrial clustering is facilitated by SQSTM/p62. We show that phosphorylated TBK1 is recruited to the clustered mitochondria. Moreover, induced mitophagy activity is reduced in HEK293 FlpIn TRIM27 Knock Out cells, while re-introduction of EGFP-TRIM27 completely restores the mitophagy activity. Inhibition of TBK1 reduces mitophagy in HEK293 FlpIn cells and in the reconstituted EGFP-TRIM27 expressing cells, but not in HEK293 FlpIn TRIM27 Knock Out cells. Altogether, these data reveal novel roles for TRIM27 in mitophagy, facilitating mitochondrial clustering via SQSTM1/p62 and mitophagy via stabilization of phosphorylated TBK1 on mitochondria.
    DOI:  https://doi.org/10.1111/febs.16628
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