Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell, 2020, Mick et al

Andy · May 29, 2020

Mitochondrial dysfunction is associated with activation of the integrated stress response (ISR) but the underlying triggers remain unclear. We systematically combined acute mitochondrial inhibitors with genetic tools for compartment-specific NADH oxidation to trace mechanisms linking different forms of mitochondrial dysfunction to the ISR in proliferating mouse myoblasts and in differentiated myotubes. In myoblasts, we find that impaired NADH oxidation upon electron transport chain (ETC) inhibition depletes asparagine, activating the ISR via the eIF2α kinase GCN2. In myotubes, however, impaired NADH oxidation following ETC inhibition neither depletes asparagine nor activates the ISR, reflecting an altered metabolic state. ATP synthase inhibition in myotubes triggers the ISR via a distinct mechanism related to mitochondrial inner-membrane hyperpolarization. Our work dispels the notion of a universal path linking mitochondrial dysfunction to the ISR, instead revealing multiple paths that depend both on the nature of the mitochondrial defect and on the metabolic state of the cell.
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Open access at https://elifesciences.org/articles/49178

Snowdrop · May 29, 2020

On the face of it this looks like it could provide important clues to information essential to understanding what's happening in ME. I hope it's as interesting / informative as it sounds.

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Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell, 2020, Mick et al

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Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell, 2020, Mick et al

Andy Committee Member

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