Warburg-like effect is a hallmark of complex I assembly defects

Publication date: Available online 20 May 2019Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Valerie Desquiret-Dumas, Geraldine Leman, Celine Wetterwald, Stephanie Chupin, Anaïs Lebert, Salim Khiati, Morgane Le Mao, Guillaume Geffroy, Mariame Selma Kane, Arnaud Chevrollier, David Goudenege, Cedric Gadras, Lydie Tessier, Magalie Barth, Stephanie Leruez, Patrizia Amati-Bonneau, Daniel Henrion, Dominique Bonneau, Vincent Procaccio, Pascal ReynierAbstractDue 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 int...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research