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. 2024 Aug;46(4):3635-3658.
doi: 10.1007/s11357-023-01059-y. Epub 2024 Jan 25.

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

Roman Abrosimov  1 , Marius W Baeken  2 , Samuel Hauf  2 , Ilka Wittig  3 , Parvana Hajieva  4 , Carmen E Perrone  5 , Bernd Moosmann  6
Affiliations

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

Roman Abrosimov et al. Geroscience. 2024 Aug.

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.

Keywords: Diabetes; FGF21; Metformin; Methionine restriction; NADH dehydrogenase; Peroxisome proliferator-activated receptor.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
NAD+-independent glucose oxidation. Complex I inhibition blocks the default pathway of glucose oxidation via glycolysis and the citric acid cycle. Consequently, intracellular glucose-6-phosphate is diverted to the pentose phosphate pathway, whose NADPH output is translated into FADH2 by fatty acid cycling. The obtained FADH2 can then be used to fuel the respiratory chain via the electron-transferring flavoprotein (ETF) complex
Fig. 2
Fig. 2
Gene expression changes of citrate shuttle enzymes after complex I inhibition by MPP in vitro. The depicted circuitry of the citrate shuttle represents its most widely discussed variant involving cytosolic oxaloacetate recycling as pyruvate. The mitochondrial citrate transporter SLC25A1 accepts different polyanions as exchange substrates, canonically malate (to be recycled to the cytosol by SLC25A10 in exchange for phosphate; not shown), but also phosphoenolpyruvate (PEP), succinate, and isocitrate [74]. PEP may play a primary role in the export of citrate after complex I inhibition because its import does not involve the accidental co-import of reducing equivalents into the already NADH-overloaded mitochondrion. Abbreviations are used as in Table 2. Expression fold changes after MPP treatment are given in brackets; n.s., not significant
Fig. 3
Fig. 3
Tissue-integrating sketch of key changes in gene expression and metabolite concentrations induced by methionine restriction in vivo. Methionine restriction leads to a systematic shift away from glycolysis towards fatty acid uptake and β-oxidation in the liver (liv). In adipose tissue (adi), there is a complementary induction of glucose degradation, fatty acid synthesis and fatty acid provision for export. Fatty acid uptake and oxidation are also induced in skeletal muscle (mus). In case of an incomplete inhibition of complex I in the liver, both metabolic axes (left/right) may be operable in parallel
Fig. 4
Fig. 4
Distribution of fatty acid cycling between the liver and adipose tissue in vivo. Inter-tissue transport processes to maintain fatty acid cycling following hepatic complex I inhibition include the transfer of de novo synthesized fatty acids (e.g., stearate) from adipose tissue to the liver, and the return of acetyl-CoA units from the liver to adipose tissue in the form of ketones (e.g., β-hydroxybutyrate). Complete redox cofactor neutrality would be achieved if the surplus hepatic NADH from β-oxidation were also transported to the adipose tissue via the lactate-pyruvate shuttle as shown. The two core elements of the NADPH-FADH2 axis that are connected by fatty acid cycling are boxed in red
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References

    1. Abu-Elheiga L, Brinkley WR, Zhong L, Chirala SS, Woldegiorgis G, Wakil SJ. The subcellular localization of acetyl-CoA carboxylase 2. Proc Natl Acad Sci U S A. 2000;97(4):1444–1449. doi: 10.1073/pnas.97.4.1444. - DOI - PMC - PubMed
    1. Arnold PK, Finley LWS. Regulation and function of the mammalian tricarboxylic acid cycle. J Biol Chem. 2023;299(2):102838. doi: 10.1016/j.jbc.2022.102838. - DOI - PMC - PubMed
    1. Arruda AC, Perilhão MS, Santos WA, Gregnani MF, Budu A, Neto JCR, Estrela GR, Araujo RC. PPARα-dependent modulation by metformin of the expression of OCT-2 and MATE-1 in the kidney of mice. Molecules. 2020;25(2):392. doi: 10.3390/molecules25020392. - DOI - PMC - PubMed
    1. Arzumanian VA, Kiseleva OI, Poverennaya EV. The curious case of the HepG2 cell line: 40 years of expertise. Int J Mol Sci. 2021;22(23):13135. doi: 10.3390/ijms222313135. - DOI - PMC - PubMed
    1. Baeken MW, Koetzner P, Richly H, Behl C, Moosmann B, Hajieva P. Adaptive epigenetic regulation of neuronal metabolism by a mitochondrial redox signal. BioRxiv. 2023;570533. 10.1101/2023.12.10.570533v1

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