Vamsi K. Mootha

TL;DR: The findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes, and suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria.

TL;DR: This work 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, revealing multiple paths that depend both on the nature of the mitochondrial defect and on the metabolic state of the cell.

TL;DR: By combining enzymology, structural biology, and activity-based metabolomics, this work reports that CLYBL operates as a citramalyl-CoA lyase in mammalian cells and reveals that a consequence of exposure to the immunomodulatory metabolite itaconate is B12 inactivation.

TL;DR: Perhaps paradoxically, certain forms of mitochondrial dysfunction may best be buffered with "second site" inhibitors to the organelle, which benefits cells by rebalancing redox cofactors, increasing reductive carboxylation, and promoting glycolysis.

TL;DR: It is demonstrated that NADH reductive stress mediates the effects of GCKR variation on many metabolic traits, including circulating triglyceride levels, glucose tolerance and FGF21 levels, and underscores the utility of genetic tools such as Lb NOX to empower studies of 'causal metabolism’.