bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–10–06
seven papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. The role of PINK1-Parkin in mitochondrial quality control.
  2. SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
  3. Mitochondria: the beating heart of the eukaryotic cell.
  4. Temporal alterations of the nascent proteome in response to mitochondrial stress.
  5. Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.
  6. Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging.
  7. Reassessing kinetin's effect on PINK1 and mitophagy.
  1. Nat Cell Biol. 2024 Oct 02.
    The role of PINK1-Parkin in mitochondrial quality control.
    Derek P Narendra, Richard J Youle.
      Mitophagy mediated by the recessive Parkinson's disease genes PINK1 and Parkin responds to mitochondrial damage to preserve mitochondrial function. In the pathway, PINK1 is the damage sensor, probing the integrity of the mitochondrial import pathway, and activating Parkin when import is blocked. Parkin is the effector, selectively marking damaged mitochondria with ubiquitin for mitophagy and other quality-control processes. This selective mitochondrial quality-control pathway may be especially critical for dopamine neurons affected in Parkinson's disease, in which the mitochondrial network is widely distributed throughout a highly branched axonal arbor. Here we review the current understanding of the role of PINK1-Parkin in the quality control of mitophagy, including sensing of mitochondrial distress by PINK1, activation of Parkin by PINK1 to induce mitophagy, and the physiological relevance of the PINK1-Parkin pathway.
    DOI:  https://doi.org/10.1038/s41556-024-01513-9
  2. Sci Adv. 2024 Oct 04. 10(40): eadq6223
    SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
    Richard Seager, Nitheyaa Shree Ramesh, Stephen Cross, Chun Guo, Kevin A Wilkinson, Jeremy M Henley.
      Mitochondria undergo fragmentation in response to bioenergetic stress, mediated by dynamin-related protein 1 (DRP1) recruitment to the mitochondria. The major pro-fission DRP1 receptor is mitochondrial fission factor (MFF), and mitochondrial dynamics proteins of 49 and 51 kilodaltons (MiD49/51), which can sequester inactive DRP1. Together, they form a trimeric DRP1-MiD-MFF complex. Adenosine monophosphate-activated protein kinase (AMPK)-mediated phosphorylation of MFF is necessary for mitochondrial fragmentation, but the molecular mechanisms are unclear. Here, we identify MFF as a target of small ubiquitin-like modifier (SUMO) at Lys151, MFF SUMOylation is enhanced following AMPK-mediated phosphorylation and that MFF SUMOylation regulates the level of MiD binding to MFF. The mitochondrial stressor carbonyl cyanide 3-chlorophenylhydrazone (CCCP) promotes MFF SUMOylation and mitochondrial fragmentation. However, CCCP-induced fragmentation is impaired in MFF-knockout mouse embryonic fibroblasts expressing non-SUMOylatable MFF K151R. These data suggest that the AMPK-MFF SUMOylation axis dynamically controls stress-induced mitochondrial fragmentation by regulating the levels of MiD in trimeric fission complexes.
    DOI:  https://doi.org/10.1126/sciadv.adq6223
  3. FEBS Open Bio. 2024 Oct;14(10): 1588-1590
    Mitochondria: the beating heart of the eukaryotic cell.
    Johannes M Herrmann.
      Mitochondria are essential organelles of eukaryotic cells. They consist of hundreds of proteins, which are synthesized in the cytosol and imported into mitochondria via different targeting routes. In addition, a small number of proteins are encoded by the organellar genome and synthesized by mitochondrial ribosomes. In this 'In the Limelight' special issue of FEBS Open Bio, five review articles describe these different biogenesis routes of mitochondrial proteins and provide a comprehensive overview of the structures and mechanisms by which mitochondrial proteins are synthesized and transported to their respective location within the organelle. These reviews, written by leading experts, provide a general overview, but also highlight current developments in the field of mitochondrial biogenesis.
    DOI:  https://doi.org/10.1002/2211-5463.13884
  4. Cell Rep. 2024 Oct 02. pii: S2211-1247(24)01154-9. [Epub ahead of print]43(10): 114803
    Temporal alterations of the nascent proteome in response to mitochondrial stress.
    Tomasz M Stępkowski, Vanessa Linke, Dorota Stadnik, Maciej Zakrzewski, Anna E Zawada, Remigiusz A Serwa, Agnieszka Chacinska.
      Under stress, protein synthesis is attenuated to preserve energy and mitigate challenges to protein homeostasis. Here, we describe, with high temporal resolution, the dynamic landscape of changes in the abundance of proteins synthesized upon stress from transient mitochondrial inner membrane depolarization. This nascent proteome was altered when global translation was attenuated by stress and began to normalize as translation was recovering. This transition was associated with a transient desynchronization of cytosolic and mitochondrial translation and recovery of cytosolic and mitochondrial ribosomal proteins. Further, the elongation factor EEF1A1 was downregulated upon mitochondrial stress, and its silencing mimicked the stress-induced nascent proteome remodeling, including alterations in the nascent respiratory chain proteins. Unexpectedly, the stress-induced alterations in the nascent proteome were independent of physiological protein abundance and turnover. In summary, we provide insights into the physiological and pathological consequences of mitochondrial function and dysfunction.
    Keywords:  CP: Cell biology; CP: Metabolism; EEF1A; EEF1A1; cellular stress; elongation factor; mass spectrometry; mitochondria; nascent chain; protein synthesis; proteomics; translation
    DOI:  https://doi.org/10.1016/j.celrep.2024.114803
  5. Cell Rep. 2024 Sep 28. pii: S2211-1247(24)01145-8. [Epub ahead of print]43(10): 114794
    Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.
    Gan Zhao, Mingkang Jia, Shicong Zhu, He Ren, Guopeng Wang, Guangwei Xin, Mengjie Sun, Xiangyang Wang, Qiaoyu Lin, Qing Jiang, Chuanmao Zhang.
      Cell division is tightly regulated and requires an expanded energy supply. However, how this energy is generated remains unclear. Here, we establish a correlation between two mitochondrial Ca2+ influx events and ATP production during mitosis. While both events promote ATP production during mitosis, the second event, the Ca2+ influx surge, is substantial. To facilitate this Ca2+ influx surge, the lamin B receptor (LBR) organizes a mitosis-specific endoplasmic reticulum (ER)-mitochondrial contact site (ERMCS), creating a rapid Ca2+ transport pathway. LBR acts as a tether, connecting the ER Ca2+ release channel IP3R with the mitochondrial VDAC2. Depletion of LBR disrupts the Ca2+ influx surge, reduces ATP production, and postpones the metaphase-anaphase transition and subsequent cell division. These findings provide insight into the mechanisms underlying mitotic energy production and supply required for cell proliferation.
    Keywords:  CP: Cell biology; CP: Metabolism; Ca(2+); ER-mitochondrial contact; LBR; VDAC2; cell cycle; cell division; energy generation; metaphase-anaphase transition; mitochondria; mitosis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114794
  6. EMBO J. 2024 Oct 04.
    Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging.
    Anna Rappe, Helena A Vihinen, Fumi Suomi, Antti J Hassinen, Homa Ehsan, Eija S Jokitalo, Thomas G McWilliams.
      Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated in age-related neurodegenerative disorders such as Parkinson's and Alzheimer's disease. While mitophagy decreases throughout the lifespan of short-lived model organisms, it remains unknown whether such a decline occurs in the aging mammalian brain-a question of fundamental importance for understanding cell type- and region-specific susceptibility to neurodegeneration. Here, we define the longitudinal dynamics of basal mitophagy and macroautophagy across neuronal and non-neuronal cell types within the intact aging mouse brain in vivo. Quantitative profiling of reporter mouse cohorts from young to geriatric ages reveals cell- and tissue-specific alterations in mitophagy and macroautophagy between distinct subregions and cell populations, including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia and interneurons. We also find that healthy aging is hallmarked by the dynamic accumulation of differentially acidified lysosomes in several neural cell subsets. Our findings argue against any widespread age-related decline in mitophagic activity, instead demonstrating dynamic fluctuations in mitophagy across the aging trajectory, with strong implications for ongoing theragnostic development.
    Keywords:  Aging; Autophagy; Brain; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.1038/s44318-024-00241-y
  7. Autophagy. 2024 Sep 29. 1-2
    Reassessing kinetin's effect on PINK1 and mitophagy.
    Zhong Yan Gan, David Komander, Sylvie Callegari.
      Substantial evidence indicates that a decline in mitochondrial health contributes to the development of Parkinson disease. Accordingly, therapeutic stimulation of mitophagy, the autophagic turnover of dysfunctional mitochondria, is a promising approach to treat Parkinson disease. An attractive target in such a setting is PINK1, a protein kinase that initiates the mitophagy cascade. Previous reports suggest that PINK1 kinase activity can be enhanced by kinetin triphosphate (KTP), an enlarged ATP analog that acts as an alternate phosphate donor for PINK1 during phosphorylation. However, the mechanism of how KTP could exert such an effect on PINK1 was unclear. In a recent study, we demonstrate that contrary to previous thinking, KTP cannot be used by PINK1. Nucleotide-bound PINK1 structures indicate that KTP would clash with the back of PINK1's ATP binding pocket, and enlarging this pocket by mutagenesis is required to enable PINK1 to use KTP. Strikingly, mutation shifts PINK1's nucleotide preference from ATP to KTP. Similar results could be demonstrated in cells with kinetin, a membrane-permeable precursor of KTP. These results overturn the previously accepted mechanism of how kinetin enhances mitophagy and indicate that kinetin and its derivatives instead function through a currently unidentified mechanism.
    Keywords:  Mitophagy; PINK1; parkin; parkinson’s disease; protein kinase; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2024.2395144
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