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Nix induced mitochondrial fission and mitophagy inhibits myocyte insulin signaling through mTOR and p70S6 kinase
Author(s) -
Gordon Joseph W.,
da Silva Rosa Simone Cristina,
Field Jared T.,
Martens Matthew D.,
West Adrian R.,
Aliani Michel,
Dolinsky Ver W.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04070
Subject(s) - mitophagy , lipotoxicity , autophagy , biology , mitochondrial fission , insulin resistance , microbiology and biotechnology , myocyte , phosphatidic acid , mitochondrion , pi3k/akt/mtor pathway , medicine , endocrinology , insulin , signal transduction , biochemistry , apoptosis , phospholipid , membrane
Lipotoxicity is a form of cellular stress caused by the accumulation of lipids resulting in mitochondrial dysfunction and insulin resistance in muscle. Previously, we demonstrated that the mitophagy receptor Nix is responsive to lipotoxicity and accumulates in response to diacylglycerols induced by high‐fat (HF) feeding. In addition, previous studies have implicated autophagy and mitophagy in muscle insulin sensitivity. To provide a better understanding of these observations, we undertook gene expression array and shot‐gun metabolomics studies in soleus muscle from rodents on an HF diet. Interestingly, we observed a modest reduction in several autophagy‐related genes including Beclin‐1, ATG3, and ‐5. Moreover, we observed alterations in the fatty acyl composition of cardiolipins and phosphatidic acids. Given the previously reported roles of these phospholipids and Nix in mitochondrial dynamics, we investigated aberrant mitochondrial fission and turn‐over as a mechanism of myocyte insulin resistance. In a series of gain‐of‐function and loss‐of‐function experiments in rodent and human myotubes, we demonstrate that Nix accumulation triggers mitochondrial depolarization, fragmentation, calcium‐dependent activation of DRP1, and mitophagy. In addition, Nix‐induced mitochondrial fission leads to myotube insulin resistance through activation of mTOR‐p70S6 kinase and inhibition of IRS1, which is contingent on phosphatidic acids and Rheb1. These findings provide insight into the role of Nix‐induced mitophagy and myocyte insulin resistance during an overfed state when overall autophagy‐related gene expression is reduced. Support or Funding Information Funded by Research Manitoba, the Children’s Hospital Research Institute of Manitoba, and the Diabetes Research Envisioned and Accomplish in Manitoba (DREAM) theme.