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

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 1:1 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.

Antioxidant and prooxidant modulation of lipid peroxidation by integral membrane proteins.

Lipid peroxidation is a biochemically adverse phenomenon with key involvement in many different diseases including premature infant blindness, nonalcoholic steatohepatitis, or Parkinson's disease. Moreover, lipid peroxidation may be the most important universal driver of the biological aging process. Canonic lipid peroxidation is a free radical chain reaction consisting of three kinetically independent steps, initiation, propagation, and termination. During the bulk propagation phase, only lipids and oxygen are consumed as substrates and maintain the chain reaction. In native biological membranes, however, lipid peroxidation takes place in direct vicinity to high concentrations of inserted membrane proteins with their exposed hydrophobic amino acid side chains. In the following, we review the evidence that redox-active intramembrane amino acid residues have a profound impact on the course and extent of lipid peroxidation in vivo. Specifically, tyrosine and tryptophan are concluded to be chain-breaking antioxidants that effectuate termination, whereas cysteine is a chain-transfer catalyst that accelerates propagation and thereby promotes lipid peroxidation. Methionine, in turn, is highly accumulated in mitochondrial membrane proteins of animal species with high metabolic rates and imminent danger of lipid peroxidation, though its specific role has not been entirely defined. Potentially, it interferes with initiation on the membrane protein surface. Nevertheless, all four residues are distinguished by their clear relevance to lipid peroxidation as deduced from either experimental or genetic and comparative data. The latter have uncovered distinct evolutionary pressures in favor or against each residue in lipid membranes and have shed light on formerly unacknowledged chemical mechanisms.