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 appearing highly paradoxical in a state of mitochondrial impairment. However, concomitant induction of catabolic fatty acid oxidation indicated that complex I inhibition created a "futile" cycle of fatty acid synthesis and degradation, which was anatomically distributed between adipose tissue and liver in vivo. Cofactor balance analysis unveiled that such cycling would indeed be energetically futile (-3 ATP per acetyl-CoA), though it would not be redox-futile, as it would convert NADPH into respirable FADH2 without any net production of NADH. We conclude that inhibition of NADH dehydrogenase leads to a metabolic shift from glycolysis and the citric acid cycle (both generating NADH) towards the pentose phosphate pathway, whose product NADPH is translated 11 into FADH2 by fatty acid cycling. The diabetes-resistant phenotype following hepatic and intestinal complex I inhibition is attributed to FGF21- and GDF15-dependent fat hunger signaling, which remodels adipose tissue into a glucose-metabolizing organ.