Washington University in St. Louis

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Metabolomics to elucidate novel biochemical mechanisms of disease
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Mitochondrial Fusion Supports Increased Oxidative Phosphorylation During Cell Proliferation

Yao C-H, Wang R, Wang Y, Kung C-P, Weber JD, and Patti GJ
Mitochondrial Fusion Supports Increased Oxidative Phosphorylation During Cell Proliferation
eLife, 8:e41351, 2019
doi:10.7554/eLife.41351

Proliferating cells often have increased glucose consumption and lactate excretion relative to the same cells in the quiescent state, a phenomenon known as the Warburg effect. Despite an increase in glycolysis, however, here we show that non-transformed mouse fibroblasts also increase oxidative phosphorylation (OXPHOS) by nearly two-fold and mitochondrial coupling efficiency by ~30% during proliferation. Both increases are supported by mitochondrial fusion. Impairing mitochondrial fusion by knocking down mitofusion-2 (Mfn2) was sufficient to attenuate proliferation, while overexpressing Mfn2 increased proliferation. Interestingly, impairing mitochondrial fusion decreased OXPHOS but did not deplete ATP levels. Instead, inhibition caused cells to transition from excreting aspartate to consuming it. Transforming fibroblasts with the Ras oncogene induced mitochondrial biogenesis, which further elevated OXPHOS. Notably, transformed fibroblasts continued to have elongated mitochondria and their proliferation remained sensitive to inhibition of Mfn2. Our results suggest that cell proliferation requires increased OXPHOS as supported by mitochondrial fusion.

Washington University, Departments of Chemistry, Genetics, and Medicine. Saint Louis, Missouri 63110 USA