Abstract
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.
Highlights
Depending on cell type and microenvironment, various adaptations in metabolism have been associated with cellular proliferation
We applied a well-controlled fibroblast model to quantify changes in mitochondrial respiration that occur in quiescent cells, nontransformed proliferating cells, and transformed proliferating cells
Despite the frequent assumption that increased glycolysis in cells exhibiting the Warburg effect is associated with decreased oxidative phosphorylation (OXPHOS), we found that mitochondrial respiration increased by nearly two-fold in non-transformed proliferating cells relative to quiescent cells
Summary
Depending on cell type and microenvironment, various adaptations in metabolism have been associated with cellular proliferation. Cancer Biology Cell Biology eLife digest Most cells in the body contain many small compartments called mitochondria These tiny powerhouses can use oxygen to break down molecules of glucose (a type of sugar) and release the energy that fuels many life processes. Mitochondria can use oxygen to build certain compounds essential for the cell Dividing cells, such as the ones found in tumors, need a lot of energy. They often ‘choose’ to burn much of their glucose through fermentation, a less efficient process that does not require oxygen or mitochondria. Further experiments reveal that, in both cancerous and healthy cells, the different mitochondria inside a cell merge during periods of intense division This mechanism allows the compartment to better use oxygen. Our results indicate that proliferation of fibroblasts requires an increase in OXPHOS supported by mitochondrial fusion
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