bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–07–14
ten papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. The caspase-activated DNase promotes cellular senescence.
  2. Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.
  3. A roadmap for ribosome assembly in human mitochondria.
  4. Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
  5. GRP75-dependent mitochondria-ER contacts ensure cell survival during early mouse thymocyte development.
  6. PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4.
  7. Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
  8. PINK1 regulated mitophagy is evident in skeletal muscles.
  9. Egg multivesicular bodies elicit an LC3-associated phagocytosis-like pathway to degrade paternal mitochondria after fertilization.
  10. Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes.
  1. EMBO J. 2024 Jul 08.
    The caspase-activated DNase promotes cellular senescence.
    Aladin Haimovici, Valentin Rupp, Tarek Amer, Abdul Moeed, Arnim Weber, Georg Häcker.
      Cellular senescence is a response to many stressful insults. DNA damage is a consistent feature of senescent cells, but in many cases its source remains unknown. Here, we identify the cellular endonuclease caspase-activated DNase (CAD) as a critical factor in the initiation of senescence. During apoptosis, CAD is activated by caspases and cleaves the genomic DNA of the dying cell. The CAD DNase is also activated by sub-lethal signals in the apoptotic pathway, causing DNA damage in the absence of cell death. We show that sub-lethal signals in the mitochondrial apoptotic pathway induce CAD-dependent senescence. Inducers of cellular senescence, such as oncogenic RAS, type-I interferon, and doxorubicin treatment, also depend on CAD presence for senescence induction. By directly activating CAD experimentally, we demonstrate that its activity is sufficient to induce senescence in human cells. We further investigate the contribution of CAD to senescence in vivo and find substantially reduced signs of senescence in organs of ageing CAD-deficient mice. Our results show that CAD-induced DNA damage in response to various stimuli is an essential contributor to cellular senescence.
    Keywords:  Ageing; Apoptosis; Caspase-activated DNase; Senescence
    DOI:  https://doi.org/10.1038/s44318-024-00163-9
  2. Mol Cell. 2024 Jun 28. pii: S1097-2765(24)00512-4. [Epub ahead of print]
    Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.
    Johannes Pilic, Benjamin Gottschalk, Benjamin Bourgeois, Hansjörg Habisch, Zhanat Koshenov, Furkan E Oflaz, Yusuf C Erdogan, Seyed M Miri, Esra N Yiğit, Mehmet Ş Aydın, Gürkan Öztürk, Emrah Eroglu, Varda Shoshan-Barmatz, Tobias Madl, Wolfgang F Graier, Roland Malli.
      Metabolic enzymes can adapt during energy stress, but the consequences of these adaptations remain understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, forms rings around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and mitochondrial dynamics protein (MiD51). HK1-rings prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial fission factor (Mff) and mitochondrial fission 1 protein (Fis1). The disassembly of HK1-rings during energy restoration correlated with mitochondrial fission. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the formation of HK1-rings. Mutations that affect the formation of HK1-rings showed that HK1-rings rewire cellular metabolism toward increased TCA cycle activity. Our findings highlight that HK1 is an energy stress sensor that regulates the shape, connectivity, and metabolic activity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy-stress-related pathologies.
    Keywords:  ER-mitochondria contact sites; energy stress; glucose starvation; glycolysis; hexokinase; live-cell imaging; mitochondrial constriction; mitochondrial fission; non-catalytic functions; protein cluster
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.009
  3. Nat Struct Mol Biol. 2024 Jul 11.
    A roadmap for ribosome assembly in human mitochondria.
    Elena Lavdovskaia, Elisa Hanitsch, Andreas Linden, Martin Pašen, Venkatapathi Challa, Yehor Horokhovskyi, Hanna P Roetschke, Franziska Nadler, Luisa Welp, Emely Steube, Marleen Heinrichs, Mandy Mong-Quyen Mai, Henning Urlaub, Juliane Liepe, Ricarda Richter-Dennerlein.
      Mitochondria contain dedicated ribosomes (mitoribosomes), which synthesize the mitochondrial-encoded core components of the oxidative phosphorylation complexes. The RNA and protein components of mitoribosomes are encoded on two different genomes (mitochondrial and nuclear) and are assembled into functional complexes with the help of dedicated factors inside the organelle. Defects in mitoribosome biogenesis are associated with severe human diseases, yet the molecular pathway of mitoribosome assembly remains poorly understood. Here, we applied a multidisciplinary approach combining biochemical isolation and analysis of native mitoribosomal assembly complexes with quantitative mass spectrometry and mathematical modeling to reconstitute the entire assembly pathway of the human mitoribosome. We show that, in contrast to its bacterial and cytosolic counterparts, human mitoribosome biogenesis involves the formation of ribosomal protein-only modules, which then assemble on the appropriate ribosomal RNA moiety in a coordinated fashion. The presence of excess protein-only modules primed for assembly rationalizes how mitochondria cope with the challenge of forming a protein-rich ribonucleoprotein complex of dual genetic origin. This study provides a comprehensive roadmap of mitoribosome biogenesis, from very early to late maturation steps, and highlights the evolutionary divergence from its bacterial ancestor.
    DOI:  https://doi.org/10.1038/s41594-024-01356-w
  4. Dev Cell. 2024 Jul 03. pii: S1534-5807(24)00386-1. [Epub ahead of print]
    Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
    Daisuke Murata, Shubhrajit Roy, Svetlana Lutsenko, Miho Iijima, Hiromi Sesaki.
      Following the Goldilocks principle, mitochondria size must be "just right." Mitochondria balance division and fusion to avoid becoming too big or too small. Defects in this balance produce dysfunctional mitochondria in human diseases. Mitochondrial safeguard (MitoSafe) is a defense mechanism that protects mitochondria against extreme enlarging by suppressing fusion in mammalian cells. In MitoSafe, hyperfused mitochondria elicit flickering-short pulses of mitochondrial depolarization. Flickering activates an inner membrane protease, Oma1, which in turn proteolytically inactivates a mitochondrial fusion protein, Opa1. The mechanisms underlying flickering are unknown. Using a live-imaging screen, we identified Slc25a3 (a mitochondrial carrier transporting phosphate and copper) as necessary for flickering and Opa1 cleavage. Remarkably, copper, but not phosphate, is critical for flickering. Furthermore, we found that two copper-containing mitochondrial enzymes, superoxide dismutase 1 and cytochrome c oxidase, regulate flickering. Our data identify an unforeseen mechanism linking copper, redox homeostasis, and membrane flickering in mitochondrial defense against deleterious fusion.
    Keywords:  division; fusion; mitochondria; stress response; transporter
    DOI:  https://doi.org/10.1016/j.devcel.2024.06.008
  5. Dev Cell. 2024 Jul 03. pii: S1534-5807(24)00385-X. [Epub ahead of print]
    GRP75-dependent mitochondria-ER contacts ensure cell survival during early mouse thymocyte development.
    Fan Zhao, Zejin Cui, Pengfei Wang, Zhishan Zhao, Kaixiang Zhu, Yadan Bai, Xuexiao Jin, Lie Wang, Linrong Lu.
      Mitochondria and endoplasmic reticulum contacts (MERCs) control multiple cellular processes, including cell survival and differentiation. Based on the observations that MERCs were specifically enriched in the CD4-CD8- double-negative (DN) stage, we studied their role in early mouse thymocyte development. We found that T cell-specific knockout of Hspa9, which encodes GRP75, a protein that mediates MERC formation by assembling the IP3R-GRP75-VDAC complex, impaired DN3 thymocyte viability and resulted in thymocyte developmental arrest at the DN3-DN4 transition. Mechanistically, GRP75 deficiency induced mitochondrial stress, releasing mitochondrial DNA (mtDNA) into the cytosol and triggering the type I interferon (IFN-I) response. The IFN-I pathway contributed to both the impairment of cell survival and DN3-DN4 transition blockage, while increased lipid peroxidation (LPO) played a major role downstream of IFN-I. Thus, our study identifies the essential role of GRP75-dependent MERCs in early thymocyte development and the governing facts of cell survival and differentiation in the DN stage.
    Keywords:  GRP75; IFN-I; cell survival; mitochondria-ER contacts; thymocyte development
    DOI:  https://doi.org/10.1016/j.devcel.2024.06.007
  6. EMBO Rep. 2024 Jul 11.
    PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4.
    Giang Thanh Nguyen-Dien, Brendan Townsend, Prajakta Gosavi Kulkarni, Keri-Lyn Kozul, Soo Siang Ooi, Denaye N Eldershaw, Saroja Weeratunga, Meihan Liu, Mathew Jk Jones, S Sean Millard, Dominic Ch Ng, Michele Pagano, Alexis Bonfim-Melo, Tobias Schneider, David Komander, Michael Lazarou, Brett M Collins, Julia K Pagan.
      Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both steady-state and induced mitophagy. Disruption of the phosphatase activity of PPTC7 does not influence BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homoeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-BNIP3/NIX and PPTC7-FBXL4 interactions and their disruption interferes with both BNIP3/NIX degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts BNIP3/NIX-induced mitophagy.
    Keywords:  BNIP3; FBXL4; Mitophagy; NIX; PPTC7
    DOI:  https://doi.org/10.1038/s44319-024-00181-y
  7. Life Sci Alliance. 2024 Sep;pii: e202402765. [Epub ahead of print]7(9):
    Dual-localized PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
    Lianjie Wei, Mehmet Oguz Gok, Jordyn D Svoboda, Keri-Lyn Kozul, Merima Forny, Jonathan R Friedman, Natalie M Niemi.
      PPTC7 is a mitochondrial-localized phosphatase that suppresses BNIP3- and NIX-mediated mitophagy, but the mechanisms underlying this regulation remain ill-defined. Here, we demonstrate that loss of PPTC7 upregulates BNIP3 and NIX post-transcriptionally and independent of HIF-1α stabilization. Loss of PPTC7 prolongs the half-life of BNIP3 and NIX while blunting their accumulation in response to proteasomal inhibition, suggesting that PPTC7 promotes the ubiquitin-mediated turnover of BNIP3 and NIX. Consistently, overexpression of PPTC7 limits the accumulation of BNIP3 and NIX protein levels, which requires an intact catalytic motif but is surprisingly independent of its targeting to mitochondria. Consistently, we find that PPTC7 is dual-localized to the outer mitochondrial membrane and the matrix. Importantly, anchoring PPTC7 to the outer mitochondrial membrane is sufficient to blunt BNIP3 and NIX accumulation, and proximity labeling and fluorescence co-localization experiments demonstrate that PPTC7 dynamically associates with BNIP3 and NIX within the native cellular environment. Collectively, these data reveal that a fraction of PPTC7 localizes to the outer mitochondrial membrane to promote the proteasomal turnover of BNIP3 and NIX, limiting basal mitophagy.
    DOI:  https://doi.org/10.26508/lsa.202402765
  8. Autophagy Rep. 2024 Mar 11. 3(1): 2326402
    PINK1 regulated mitophagy is evident in skeletal muscles.
    Francois Singh, Lea Wilhelm, Alan R Prescott, Kevin Ostacolo, Jin-Feng Zhao, Margret H Ogmundsdottir, Ian G Ganley.
      PINK1, mutated in familial forms of Parkinson's disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.
    Keywords:  PINK1; POLG; Parkinson’s; mitophagy; muscle; mutator
    DOI:  https://doi.org/10.1080/27694127.2024.2326402
  9. Nat Commun. 2024 Jul 08. 15(1): 5715
    Egg multivesicular bodies elicit an LC3-associated phagocytosis-like pathway to degrade paternal mitochondria after fertilization.
    Sharon Ben-Hur, Shoshana Sernik, Sara Afar, Alina Kolpakova, Yoav Politi, Liron Gal, Anat Florentin, Ofra Golani, Ehud Sivan, Nili Dezorella, David Morgenstern, Shmuel Pietrokovski, Eyal Schejter, Keren Yacobi-Sharon, Eli Arama.
      Mitochondria are maternally inherited, but the mechanisms underlying paternal mitochondrial elimination after fertilization are far less clear. Using Drosophila, we show that special egg-derived multivesicular body vesicles promote paternal mitochondrial elimination by activating an LC3-associated phagocytosis-like pathway, a cellular defense pathway commonly employed against invading microbes. Upon fertilization, these egg-derived vesicles form extended vesicular sheaths around the sperm flagellum, promoting degradation of the sperm mitochondrial derivative and plasma membrane. LC3-associated phagocytosis cascade of events, including recruitment of a Rubicon-based class III PI(3)K complex to the flagellum vesicular sheaths, its activation, and consequent recruitment of Atg8/LC3, are all required for paternal mitochondrial elimination. Finally, lysosomes fuse with strings of large vesicles derived from the flagellum vesicular sheaths and contain degrading fragments of the paternal mitochondrial derivative. Given reports showing that in some mammals, the paternal mitochondria are also decorated with Atg8/LC3 and surrounded by multivesicular bodies upon fertilization, our findings suggest that a similar pathway also mediates paternal mitochondrial elimination in other flagellated sperm-producing organisms.
    DOI:  https://doi.org/10.1038/s41467-024-50041-5
  10. Nat Commun. 2024 Jul 10. 15(1): 5818
    Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes.
    Kazuhiro Yamada, Claudette St Croix, Donna B Stolz, Yulia Y Tyurina, Vladimir A Tyurin, Laura R Bradley, Alexander A Kapralov, Yanhan Deng, Xiuxia Zhou, Qi Wei, Bo Liao, Nobuhiko Fukuda, Mara Sullivan, John Trudeau, Anuradha Ray, Valerian E Kagan, Jinming Zhao, Sally E Wenzel.
      A stable mitochondrial pool is crucial for healthy cell function and survival. Altered redox biology can adversely affect mitochondria through induction of a variety of cell death and survival pathways, yet the understanding of mitochondria and their dysfunction in primary human cells and in specific disease states, including asthma, is modest. Ferroptosis is traditionally considered an iron dependent, hydroperoxy-phospholipid executed process, which induces cytosolic and mitochondrial damage to drive programmed cell death. However, in this report we identify a lipoxygenase orchestrated, compartmentally-targeted ferroptosis-associated peroxidation process which occurs in a subpopulation of dysfunctional mitochondria, without promoting cell death. Rather, this mitochondrial peroxidation process tightly couples with PTEN-induced kinase (PINK)-1(PINK1)-Parkin-Optineurin mediated mitophagy in an effort to preserve the pool of functional mitochondria and prevent cell death. These combined peroxidation processes lead to altered epithelial cell phenotypes and loss of ciliated cells which associate with worsened asthma severity. Ferroptosis-targeted interventions of this process could preserve healthy mitochondria, reverse cell phenotypic changes and improve disease outcomes.
    DOI:  https://doi.org/10.1038/s41467-024-50222-2
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