Mitochondrial complex I inhibition triggers NAD + -independent glucose oxidation via successive NADPH formation, "futile" fatty acid cycling, and FADH 2 oxidation.

Autor: Abrosimov R; Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany., Baeken MW; Nucleic Acid Chemistry and Engineering Unit, Okinawa Institute of Science and Technology Graduate University, Onna, Okinawa, Japan., Hauf S; Nucleic Acid Chemistry and Engineering Unit, Okinawa Institute of Science and Technology Graduate University, Onna, Okinawa, Japan., Wittig I; Institute for Cardiovascular Physiology, Goethe University, Frankfurt, Germany., Hajieva P; Institute for Translational Medicine, MSH Medical School, Hamburg, Germany., Perrone CE; Orentreich Foundation for the Advancement of Science, Cold Spring-On-Hudson, NY, USA., Moosmann B; Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. moosmann@uni-mainz.de.
Jazyk: angličtina
Zdroj: GeroScience [Geroscience] 2024 Aug; Vol. 46 (4), pp. 3635-3658. Date of Electronic Publication: 2024 Jan 25.
DOI: 10.1007/s11357-023-01059-y
Abstrakt: 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 FADH 2 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 FADH 2 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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