Warburg-like effect is a hallmark of complex I assembly defects
2019
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
metabolicadaptations in CI deficiency still remains largely unknown. Here, we investigated the relationship between CI functions, its structure and the cellular
metabolismin 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
metabolicadaptation 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
metabolicreprogramming. Thus, this study provides a two-way-model of
metabolicresponses 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.
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