bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023–01–01
six papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Mitochondrial genome recovery by ATFS-1 is essential for development after starvation.
  2. Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via regulation of pyruvate dehydrogenase (PDH) phosphorylation.
  3. Mitochondria-localized lncRNA HITT inhibits fusion by attenuating formation of mitofusin-2 homo- or heterotypic complexes.
  4. GPER induces mitochondrial fission through p44/42 MAPK - Drp1 pathway in breast cancer cells.
  5. Mitochondria and peroxisomes: partners in autophagy.
  6. Mitochondrial movers and shapers: Recent insights into regulators of fission, fusion and transport.
  1. Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01771-5. [Epub ahead of print]41(13): 111875
    Mitochondrial genome recovery by ATFS-1 is essential for development after starvation.
    Nandhitha Uma Naresh, Sookyung Kim, Tomer Shpilka, Qiyuan Yang, Yunguang Du, Cole M Haynes.
      Nutrient availability regulates the C. elegans life cycle as well as mitochondrial physiology. Food deprivation significantly reduces mitochondrial genome (mtDNA) numbers and leads to aging-related phenotypes. Here we show that the bZIP (basic leucine zipper) protein ATFS-1, a mediator of the mitochondrial unfolded protein response (UPRmt), is required to promote growth and establish a functional germline after prolonged starvation. We find that recovery of mtDNA copy numbers and development after starvation requires mitochondrion-localized ATFS-1 but not its nuclear transcription activity. We also find that the insulin-like receptor DAF-2 functions upstream of ATFS-1 to modulate mtDNA content. We show that reducing DAF-2 activity represses ATFS-1 nuclear function while causing an increase in mtDNA content, partly mediated by mitochondrion-localized ATFS-1. Our data indicate the importance of the UPRmt in recovering mitochondrial mass and suggest that atfs-1-dependent mtDNA replication precedes mitochondrial network expansion after starvation.
    Keywords:  ATFS-1; C. elegans; CP: Metabolism; CP: Molecular biology; DAF-2; UPR; UPRmt; insulin receptor; mitochondria; mtDNA; starvation; stress response
    DOI:  https://doi.org/10.1016/j.celrep.2022.111875
  2. J Biol Chem. 2022 Dec 26. pii: S0021-9258(22)01280-7. [Epub ahead of print] 102837
    Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via regulation of pyruvate dehydrogenase (PDH) phosphorylation.
    Takeshi Ikizawa, Kazutaka Ikeda, Makoto Arita, Shojiro Kitajima, Tomoyoshi Soga, Hidenori Ichijo, Isao Naguro.
      A high-salt diet significantly impacts various diseases, including cancer and immune diseases. Recent studies suggest that the high-salt/hyperosmotic environment in the body may alter the chronic properties of cancer and immune cells in the disease context. However, little is known about the acute metabolic changes in hyperosmotic stress. Here, we found that hyperosmotic stress for a few minutes induces Warburg-like metabolic remodeling in HeLa and Raw264.7 cells and suppresses fatty acid oxidation. Regarding Warburg-like remodeling, we determined that the pyruvate dehydrogenase (PDH) phosphorylation status was altered bidirectionally (high in hyperosmolarity and low in hypoosmolarity) to osmotic stress in isolated mitochondria, suggesting that mitochondria themselves have an acute osmo-sensing mechanism. Additionally, we demonstrate that Warburg-like remodeling is required for HeLa cells to maintain ATP levels and survive under hyperosmotic conditions. Collectively, our findings suggest that cells exhibit acute metabolic remodeling under osmotic stress via the regulation of PDH phosphorylation by direct osmosensing within mitochondria.
    Keywords:  Acyl-carnitine; Metabolic remodeling; Mitochondria; Osmotic stress; Pyruvate dehydrogenase
    DOI:  https://doi.org/10.1016/j.jbc.2022.102837
  3. J Biol Chem. 2022 Dec 22. pii: S0021-9258(22)01268-6. [Epub ahead of print] 102825
    Mitochondria-localized lncRNA HITT inhibits fusion by attenuating formation of mitofusin-2 homo- or heterotypic complexes.
    Xingwen Wang, Yi Zhang, Qingyu Lin, Kunming Zhao, Dantong Zhu, Ying Hu.
      Long non-coding RNAs (lncRNAs) are emerging as essential players in multiple biological processes. Mitochondrial dynamics, comprising the continuous cycle of fission and fusion, are required for healthy mitochondria that function properly. Despite long-term recognition of its significance in cell-fate control, the mechanism underlying mitochondrial fusion is not completely understood, particularly regarding the involvement of lncRNAs. Here, we show that the lncRNA HITT (HIF-1α inhibitor at translation level), can specifically localize in mitochondria. Cells expressing higher levels of HITT contain fragmented mitochondria. Conversely, we show that HITT knockdown cells have more tubular mitochondria than is present in control cells. Mechanistically, we demonstrate HITT directly binds mitofusin-2 (MFN2), a core component that mediates mitochondrial outer membrane fusion, by the in vitro RNA pull-down and UV-cross-linking RNA-IP (CLIP) assays. In doing so, we found HITT disturbs MFN2 homo- or heterotypic complex formation, attenuating mitochondrial fusion. Under stress conditions, such as ultraviolet radiation, we in addition show HITT stability increases as a consequence of MiR-205 downregulation, inhibiting MFN2-mediated fusion and leading to apoptosis. Overall, our data provide significant insights into the roles of organelle (mitochondria)-specific resident lncRNAs in regulating mitochondrial fusion, and also reveal how such a mechanism controls cellular sensitivity to UV radiation-induced apoptosis.
    Keywords:  LINC00637; MFN2; apoptosis; mitochondrial dynamics; mitochondrial fusion
    DOI:  https://doi.org/10.1016/j.jbc.2022.102825
  4. Biochem Biophys Res Commun. 2022 Dec 21. pii: S0006-291X(22)01732-6. [Epub ahead of print]643 16-23
    GPER induces mitochondrial fission through p44/42 MAPK - Drp1 pathway in breast cancer cells.
    Pothuganti Rekha, Anshu Gupta, Kalali Sridivya Goud, Bidisha Biswas, Subhashith Bhattar, Gangipangi Vijayakumar, Sudhagar Selvaraju.
      Understanding GPER biology in breast cancer is rather limited in compassion to the classic estrogen receptors. Mitochondrial dynamics play a critical role in determining cell survival and death under various microenvironmental conditions. We present evidence that GPER-induce mitochondrial fission in breast cancer cells. GPER mediated mitochondrial fission through activating Drp1 by phosphorylating S616 residue and down-regulates fusion proteins Mfn1 and Mfn2 levels. GPER-induced Drp1 activation mediated by p44/42 MAPK and inhibition of this signalling axis completely reverse the mitochondrial fission induced by GPER. Further, mitochondrial fission is required for GPER-induced cell death in breast cancer cells. To conclude, GPER induces mitochondrial fission through p44/42 MAPK - Drp1 signalling, and mitochondrial fission is critical for GPER-induced cell death in breast cancer cells. GENERAL SIGNIFICANCE: First time we report GPER's role in mitochondrial dynamics in cancer cells. Mitochondrial dynamics play a critical role in cancer progression including tamoxifen resistance. Exploring a detailed mechanistic understanding of GPER signalling may help to design new therapy for advanced cancers.
    Keywords:  Breast cancer; Drp-1; GPER; MAPK; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.bbrc.2022.12.061
  5. Autophagy. 2022 Dec 26. 1-2
    Mitochondria and peroxisomes: partners in autophagy.
    Léa P Wilhelm, Ian G Ganley.
      Mitochondria, often called "the powerhouse" of the cell due to their role as the main energy supplier, regulate numerous complex processes including intracellular calcium homeostasis, reactive oxygen species (ROS) production, regulation of immune responses, and apoptosis. So, mitochondria are a fundamental metabolic hub that also control cell survival and cell death. However, they are not unique in all these functions. Indeed, peroxisomes are small cytoplasmic organelles that also ensure metabolic functions such as fatty acid oxidation and ROS production. This common relationship also extends beyond function as peroxisomes themselves can form from mitochondrial-derived precursors. Given this interconnection between mitochondria and peroxisomes involving biogenesis and function, in our recent work we determined if their turnover was also linked.
    Keywords:  Autophagy; BNIP3L; NIX; mitophagy; pexophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2155368
  6. Curr Opin Cell Biol. 2022 Dec 27. pii: S0955-0674(22)00103-X. [Epub ahead of print]80 102150
    Mitochondrial movers and shapers: Recent insights into regulators of fission, fusion and transport.
    Nida Ul Fatima, Vaishnavi Ananthanarayanan.
      Mitochondria are highly dynamic organelles that undergo rapid morphological adaptations influencing their number, transport, cellular distribution, and function, which in turn facilitate the integration of mitochondrial function with physiological changes in the cell. These mitochondrial dynamics are dependent on tightly regulated processes such as fission, fusion, and attachment to the cytoskeleton, and their defects are observed in various pathophysiological conditions including cancer, cardiovascular disease, and neurodegeneration. Various studies over the years have identified key molecular players and uncovered the mechanisms that mediate and regulate these processes and have highlighted their complexity and context-specificity. This review focuses on the recent studies that have contributed to the understanding of processes that influence mitochondrial morphology including fission, fusion, and transport in the cell.
    Keywords:  Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mitochondrial transport
    DOI:  https://doi.org/10.1016/j.ceb.2022.102150
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