bims-midtic Biomed News
on Mitochondrial dynamics and trafficking in cells
Issue of 2024–03–17
seven papers selected by
Omkar Joshi, Turku Bioscience
  1. Downregulation of Mitochondrial Fusion Protein Expression Affords Protection from Canonical Necroptosis in H9c2 Cardiomyoblasts.
  2. GRAF1 Acts as a Downstream Mediator of Parkin to Regulate Mitophagy in Cardiomyocytes.
  3. Drp1-dependent mitochondrial fragmentation mediates photoreceptor abnormalities in type 1 diabetic retina.
  4. NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia.
  5. Polarized localization of kinesin-1 and RIC-7 drives axonal mitochondria anterograde transport.
  6. The DNA-dependent protein kinase catalytic subunit promotes sepsis-induced cardiac dysfunction through disrupting INF-2-dependent mitochondrial dynamics.
  7. The movement of mitochondria in breast cancer: internal motility and intercellular transfer of mitochondria.
  1. Int J Mol Sci. 2024 Mar 02. pii: 2905. [Epub ahead of print]25(5):
    Downregulation of Mitochondrial Fusion Protein Expression Affords Protection from Canonical Necroptosis in H9c2 Cardiomyoblasts.
    Yuki Toda, Sang-Bing Ong, Toshiyuki Yano, Atsushi Kuno, Hidemichi Kouzu, Tatsuya Sato, Wataru Ohwada, Yuki Tatekoshi, Toshifumi Ogawa, Masaki Shimizu, Masaya Tanno, Masato Furuhashi.
      Necroptosis, a form of necrosis, and alterations in mitochondrial dynamics, a coordinated process of mitochondrial fission and fusion, have been implicated in the pathogenesis of cardiovascular diseases. This study aimed to determine the role of mitochondrial morphology in canonical necroptosis induced by a combination of TNFα and zVAD (TNF/zVAD) in H9c2 cells, rat cardiomyoblasts. Time-course analyses of mitochondrial morphology showed that mitochondria were initially shortened after the addition of TNF/zVAD and then their length was restored, and the proportion of cells with elongated mitochondria at 12 h was larger in TNF/zVAD-treated cells than in non-treated cells (16.3 ± 0.9% vs. 8.0 ± 1.2%). The knockdown of dynamin-related protein 1 (Drp1) and fission 1, fission promoters, and treatment with Mdivi-1, a Drp-1 inhibitor, had no effect on TNF/zVAD-induced necroptosis. In contrast, TNF/zVAD-induced necroptosis was attenuated by the knockdown of mitofusin 1/2 (Mfn1/2) and optic atrophy-1 (Opa1), proteins that are indispensable for mitochondrial fusion, and the attenuation of necroptosis was not canceled by treatment with Mdivi-1. The expression of TGFβ-activated kinase (TAK1), a negative regulator of RIP1 activity, was upregulated and the TNF/zVAD-induced RIP1-Ser166 phosphorylation, an index of RIP1 activity, was mitigated by the knockdown of Mfn1/2 or Opa1. Pharmacological TAK1 inhibition attenuated the protection afforded by Mfn1/2 and Opa1 knockdown. In conclusion, the inhibition of mitochondrial fusion increases TAK1 expression, leading to the attenuation of canonical necroptosis through the suppression of RIP1 activity.
    Keywords:  RIP1; TAK1; cardiomyocyte; mitochondrial fusion; necroptosis
    DOI:  https://doi.org/10.3390/ijms25052905
  2. Cells. 2024 Mar 04. pii: 448. [Epub ahead of print]13(5):
    GRAF1 Acts as a Downstream Mediator of Parkin to Regulate Mitophagy in Cardiomyocytes.
    Qiang Zhu, Matthew E Combs, Dawn E Bowles, Ryan T Gross, Michelle Mendiola Pla, Christopher P Mack, Joan M Taylor.
      Cardiomyocytes rely on proper mitochondrial homeostasis to maintain contractility and achieve optimal cardiac performance. Mitochondrial homeostasis is controlled by mitochondrial fission, fusion, and mitochondrial autophagy (mitophagy). Mitophagy plays a particularly important role in promoting the degradation of dysfunctional mitochondria in terminally differentiated cells. However, the precise mechanisms by which this is achieved in cardiomyocytes remain opaque. Our study identifies GRAF1 as an important mediator in PINK1-Parkin pathway-dependent mitophagy. Depletion of GRAF1 (Arhgap26) in cardiomyocytes results in actin remodeling defects, suboptimal mitochondria clustering, and clearance. Mechanistically, GRAF1 promotes Parkin-LC3 complex formation and directs autophagosomes to damaged mitochondria. Herein, we found that these functions are regulated, at least in part, by the direct binding of GRAF1 to phosphoinositides (PI(3)P, PI(4)P, and PI(5)P) on autophagosomes. In addition, PINK1-dependent phosphorylation of Parkin promotes Parkin-GRAF1-LC3 complex formation, and PINK1-dependent phosphorylation of GRAF1 (on S668 and S671) facilitates the clustering and clearance of mitochondria. Herein, we developed new phosphor-specific antibodies to these sites and showed that these post-translational modifications are differentially modified in human hypertrophic cardiomyopathy and dilated cardiomyopathy. Furthermore, our metabolic studies using serum collected from isoproterenol-treated WT and GRAF1CKO mice revealed defects in mitophagy-dependent cardiomyocyte fuel flexibility that have widespread impacts on systemic metabolism. In summary, our study reveals that GRAF1 co-regulates actin and membrane dynamics to promote cardiomyocyte mitophagy and that dysregulation of GRAF1 post-translational modifications may underlie cardiac disease pathogenesis.
    Keywords:  GRAF1; PINK1-Parkin pathway; cardiomyocytes; metabolism; mitophagy
    DOI:  https://doi.org/10.3390/cells13050448
  3. Exp Eye Res. 2024 Mar 09. pii: S0014-4835(24)00081-2. [Epub ahead of print] 109860
    Drp1-dependent mitochondrial fragmentation mediates photoreceptor abnormalities in type 1 diabetic retina.
    Shuyu Tang, Mengling Huang, Ruixuan Wang, Ming Li, Ning Dong, Ronghan Wu, Zailong Chi, Ling Gao.
      Recent studies have highlighted that retinal neurodegeneration precedes microvascular changes in diabetic retinopathy (DR), but the specific mechanisms remain unclear. Given the pivotal role of dysfunctional mitochondria and oxidative stress in early DR, our objective was to observe mitochondria-related alterations in the neural retina of type one diabetic mellitus mice with no evidence of DR (T1DM-NDR). We aimed to identify the key mitochondrial-related proteins contributing to mitochondrial injury. Our study revealed that T1DM-NDR mice exhibited outer retina thinning, including the ellipsoid zone, inner segment, and outer segment. Additionally, there was an impaired amplitude of the b-wave in electroretinogram (ERG) and a disorganized arrangement of the photoreceptor layer. In both the retina of DM mice and high glucose (HG)-treated 661w cells, mitochondria appeared swollen and fragmented, with disrupted cristae, disorganized or shortened branches in the mitochondrial network, and decreased mitochondrial membrane potential. Among the mitochondrial-related proteins, dynamin-related protein 1 (Drp1) was upregulated, and the ratio of phosphorylated Drp1 protein at serine 616 (S616) and serine 637 (S637) sites significantly increased in the retina of DM mice. The administration of Mdivi-1 ameliorated high-glucose-induced dysfunctional mitochondria, thereby protecting T1DM-NDR mice retina from morphological and functional injuries. Our findings suggest that hyperglycemia promotes Drp1-mediated mitochondrial dysfunction, which may be a significant factor in the development of DR. The inhibition of high-glucose-induced mitochondrial fission emerges as a potential and innovative intervention strategy for preventing DR.
    Keywords:  Diabetic retinopathy; Drp1; Mitochondria; Photoreceptor; T1DM
    DOI:  https://doi.org/10.1016/j.exer.2024.109860
  4. Nat Commun. 2024 Mar 13. 15(1): 2264
    NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia.
    Chih-Wei Chen, Chi Su, Chang-Yu Huang, Xuan-Rong Huang, Xiaojing Cuili, Tung Chao, Chun-Hsiang Fan, Cheng-Wei Ting, Yi-Wei Tsai, Kai-Chien Yang, Ti-Yen Yeh, Sung-Tsang Hsieh, Yi-Ju Chen, Yuxi Feng, Tony Hunter, Zee-Fen Chang.
      NME3 is a member of the nucleoside diphosphate kinase (NDPK) family localized on the mitochondrial outer membrane (MOM). Here, we report a role of NME3 in hypoxia-induced mitophagy dependent on its active site phosphohistidine but not the NDPK function. Mice carrying a knock-in mutation in the Nme3 gene disrupting NME3 active site histidine phosphorylation are vulnerable to ischemia/reperfusion-induced infarction and develop abnormalities in cerebellar function. Our mechanistic analysis reveals that hypoxia-induced phosphatidic acid (PA) on mitochondria is essential for mitophagy and the interaction of DRP1 with NME3. The PA binding function of MOM-localized NME3 is required for hypoxia-induced mitophagy. Further investigation demonstrates that the interaction with active NME3 prevents DRP1 susceptibility to MUL1-mediated ubiquitination, thereby allowing a sufficient amount of active DRP1 to mediate mitophagy. Furthermore, MUL1 overexpression suppresses hypoxia-induced mitophagy, which is reversed by co-expression of ubiquitin-resistant DRP1 mutant or histidine phosphorylatable NME3. Thus, the site-specific interaction with active NME3 provides DRP1 a microenvironment for stabilization to proceed the segregation process in mitophagy.
    DOI:  https://doi.org/10.1038/s41467-024-46385-7
  5. J Cell Biol. 2024 May 06. pii: e202305105. [Epub ahead of print]223(5):
    Polarized localization of kinesin-1 and RIC-7 drives axonal mitochondria anterograde transport.
    Youjun Wu, Chen Ding, Behrang Sharif, Alexis Weinreb, Grace Swaim, Hongyan Hao, Shaul Yogev, Shigeki Watanabe, Marc Hammarlund.
      Mitochondria transport is crucial for axonal mitochondria distribution and is mediated by kinesin-1-based anterograde and dynein-based retrograde motor complexes. While Miro and Milton/TRAK were identified as key adaptors between mitochondria and kinesin-1, recent studies suggest the presence of additional mechanisms. In C. elegans, ric-7 is the only single gene described so far, other than kinesin-1, that is absolutely required for axonal mitochondria localization. Using CRISPR engineering in C. elegans, we find that Miro is important but is not essential for anterograde traffic, whereas it is required for retrograde traffic. Both the endogenous RIC-7 and kinesin-1 act at the leading end to transport mitochondria anterogradely. RIC-7 binding to mitochondria requires its N-terminal domain and partially relies on MIRO-1, whereas RIC-7 accumulation at the leading end depends on its disordered region, kinesin-1, and metaxin2. We conclude that transport complexes containing kinesin-1 and RIC-7 polarize at the leading edge of mitochondria and are required for anterograde axonal transport in C. elegans.
    DOI:  https://doi.org/10.1083/jcb.202305105
  6. Int J Med Sci. 2024 ;21(4): 714-724
    The DNA-dependent protein kinase catalytic subunit promotes sepsis-induced cardiac dysfunction through disrupting INF-2-dependent mitochondrial dynamics.
    Mudi Ma, Hao Zhou, Ying Zhang, Woliang Yuan, Chaoxiong Chen.
      Sepsis-induced cardiomyopathy (SIC) represents a severe complication of systemic infection, characterized by significant cardiac dysfunction. This study examines the role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Inverted Formin 2 (INF2) in the pathogenesis of SIC, focusing on their impact on mitochondrial homeostasis and dynamics. Our research demonstrates that silencing DNA-PKcs alleviates lipopolysaccharide (LPS)-induced cardiomyocyte death and dysfunction. Using HL-1 cardiomyocytes treated with LPS, we observed that DNA-PKcs knockdown notably reverses LPS-induced cytotoxicity, indicating a protective role against cellular damage. This effect is further substantiated by the reduction in caspase-3 and caspase-9 activation, key markers of apoptosis, upon DNA-PKcs knockdown. Besides, our data further reveal that DNA-PKcs knockdown attenuates LPS-induced mitochondrial dysfunction, evidenced by improved ATP production, enhanced activities of mitochondrial respiratory complexes, and preserved mitochondrial membrane potential. Moreover, DNA-PKcs deletion counteracts LPS-induced shifts towards mitochondrial fission, indicating its regulatory influence on mitochondrial dynamics. Conclusively, our research elucidates the intricate interplay between DNA-PKcs and INF2 in the modulation of mitochondrial function and dynamics during sepsis-induced cardiomyopathy. These findings offer new insights into the molecular mechanisms underpinning SIC and suggest potential therapeutic targets for mitigating mitochondrial dysfunction in this critical condition.
    Keywords:  DNA-PKcs; INF2; LPS; mitochondrial homeostasis
    DOI:  https://doi.org/10.7150/ijms.91894
  7. Clin Exp Metastasis. 2024 Mar 15.
    The movement of mitochondria in breast cancer: internal motility and intercellular transfer of mitochondria.
    Sarah Libring, Emily D Berestesky, Cynthia A Reinhart-King.
      As a major energy source for cells, mitochondria are involved in cell growth and proliferation, as well as migration, cell fate decisions, and many other aspects of cellular function. Once thought to be irreparably defective, mitochondrial function in cancer cells has found renewed interest, from suggested potential clinical biomarkers to mitochondria-targeting therapies. Here, we will focus on the effect of mitochondria movement on breast cancer progression. Mitochondria move both within the cell, such as to localize to areas of high energetic need, and between cells, where cells within the stroma have been shown to donate their mitochondria to breast cancer cells via multiple methods including tunneling nanotubes. The donation of mitochondria has been seen to increase the aggressiveness and chemoresistance of breast cancer cells, which has increased recent efforts to uncover the mechanisms of mitochondrial transfer. As metabolism and energetics are gaining attention as clinical targets, a better understanding of mitochondrial function and implications in cancer are required for developing effective, targeted therapeutics for cancer patients.
    Keywords:  Breast cancer; Mitochondria; Mitochondrial transfer; Tunneling nanotubes; mtDNA
    DOI:  https://doi.org/10.1007/s10585-024-10269-3
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