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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 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.

SUBMITTER: Abrosimov R

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

REPOSITORIES: biostudies-literature

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

Abrosimov Roman R Baeken Marius W MW Hauf Samuel S Wittig Ilka I Hajieva Parvana P Perrone Carmen E CE Moosmann Bernd B

GeroScience 20240125 4

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 evaluat ...[more]

PMID: 38267672

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Project description:Diabetes was induced by treating rats with alloxan, and was confirmed by blood glucose values greater than 250 mg/dl. In perfused livers from both normal and diabetic rats, basal rates of O2 uptake were similar (120-130 mumol/h per g). In livers from diabetic rats, basal rates of glucose output of 60 mumol/h per g declined to around 20 mumol/h per g during 1 h of perfusion. Basal glucose production was abolished by pretreatment with an inhibitor of glycogen synthesis, galactosamine (1.5 g/kg), injected 3 h before perfusion. The subsequent infusion of lactate (2 mM) increased O2 uptake and glucose production about 40-50 mumol/h per g in both groups; however, the average maximal increase in glucose output was nearly twice as high in livers from normal (33 mumol/h per g) as from diabetic (18 mumol/h per g) rats. Rates of lactate uptake were also about 50% lower in livers from diabetic than from normal rats, yet rates of ketone-body formation were similar. Miniature O2 electrodes placed on periportal and pericentral regions of the liver lobule were employed to measure local rates of O2 uptake before, during and after infusion of lactate by stopping the flow of perfusate through the liver and measuring the decrease in local [O2]. Local rates of glucose production were calculated from the extra O2 consumed and the known stoichiometry between O2 uptake and glucose production from lactate. In livers from normal rats, glucose was synthesized predominantly in periportal regions of the liver lobule; however, glucose was produced exclusively in periportal regions in livers from diabetic rats. In pericentral regions, O2 uptake increased slightly in livers from normal rats, but declined significantly by 10 mumol/h per g in livers from diabetic rats. These data are consistent with the hypothesis that gluconeogenesis from lactate occurs exclusively in periportal regions of the liver lobule in livers from diabetic rats. A portion of this glucose is metabolized back to lactate in pericentral areas, leading to increased rates of glycolytic ATP production, thereby decreasing the demands for O2. This production of glucose from lactate in periportal regions, followed by conversion of glucose back into lactate in pericentral areas, raises the possibility of intercellular futile cycling, stimulated by diabetes.

Dataset Information

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

Publications

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

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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