Mitochondrial complex I inhibition triggers NAD⁺-independent glucose oxidation via successive NADPH formation, "futile" fatty acid cycling, and FADH₂ oxidation.

ABSTRACT: Inhibition of mitochondrial complex I (NADH dehydrogenase) is the primary mechanism of the antidiabetic drug metformin and various unrelated natural toxins. Complex I inhibition can also be induced by antidiabetic PPAR agonists, and it is elicited by methionine restriction, a nutritional intervention causing resistance to diabetes and obesity. Still, a comprehensible explanation to why complex I inhibition exerts antidiabetic properties and engenders metabolic inefficiency is missing. To evaluate this issue, we have systematically reanalyzed published transcriptomic datasets from MPP-treated neurons, metformin-treated hepatocytes, and methionine-restricted rats. We found that pathways leading to NADPH formation were widely induced, together with anabolic fatty acid biosynthesis, the latter

SUBMITTER: Abrosimov R 

PROVIDER: S-EPMC11226580 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature