Desquiret-Dumas 2019 Biochim Biophys Acta Mol Basis Dis
|Desquiret-Dumas V, Leman G, Wetterwald C, Chupin S, Lebert A, Khiati S, Le Mao M, Geffroy G, Kane MS, Chevrollier A, Goudenege D, Gadras C, Tessier L, Barth M, Leruez S, Amati-Bonneau P, Henrion D, Bonneau D, Procaccio V, Reynier P, Lenaers G, Gueguen N (2019) Warburg-like effect is a hallmark of complex I assembly defects. Biochim Biophys Acta Mol Basis Dis 1865:2475-89.|
Desquiret-Dumas V, Leman G, Wetterwald C, Chupin S, Lebert A, Khiati S, Le Mao M, Geffroy G, Kane MS, Chevrollier A, Goudenege D, Gadras C, Tessier L, Barth M, Leruez S, Amati-Bonneau P, Henrion D, Bonneau D, Procaccio V, Reynier P, Lenaers G, Gueguen N (2019) Biochim Biophys Acta Mol Basis Dis
Abstract: Due to its pivotal role in NADH oxidation and ATP synthesis, mitochondrial complex I (CI) emerged as a crucial regulator of cellular metabolism. A functional CI relies on the sequential assembly of nuclear- and mtDNA-encoded subunits; however, whether CI assembly status is involved in the metabolic adaptations in CI deficiency still remains largely unknown. Here, we investigated the relationship between CI functions, its structure and the cellular metabolism in 29 patient fibroblasts representative of most CI mitochondrial diseases. Our results show that, contrary to the generally accepted view, a complex I deficiency does not necessarily lead to a glycolytic switch, i.e. the so-called Warburg effect, but that this particular metabolic adaptation is a feature of CI assembly defect. By contrast, a CI functional defect without disassembly induces a higher catabolism to sustain the oxidative metabolism. Mechanistically, we demonstrate that reactive oxygen species overproduction by CI assembly intermediates and subsequent AMPK-dependent Pyruvate Dehydrogenase inactivation are key players of this metabolic reprogramming. Thus, this study provides a two-way-model of metabolic responses to CI deficiencies that are central not only in defining therapeutic strategies for mitochondrial diseases, but also in all pathophysiological conditions involving a CI deficiency.
Copyright © 2019. Published by Elsevier B.V. • Keywords: Complex I assembly, Complex I deficiency, Metabolic reprogramming, Mitochondrial metabolism, ROS production • Bioblast editor: Plangger M • O2k-Network Lab: FR Angers Gueguen N
Labels: MiParea: Respiration, Patients Pathology: Other
Organism: Human Tissue;cell: Fibroblast Preparation: Permeabilized cells, Intact cells Enzyme: Complex I, TCA cycle and matrix dehydrogenases Regulation: Aerobic glycolysis Coupling state: LEAK, ROUTINE, OXPHOS, ET Pathway: N, S, NS, ROX HRR: Oxygraph-2k, O2k-Fluorometer