Mitochondrial fusion supports increased oxidative phosphorylation during cell proliferation

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.

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 also use oxygen to build certain compounds essential for the cell.

Rapidly dividing cells, such as the ones found in tumors, need a lot of energy. Yet, they often ‘choose’ to burn much of their glucose through fermentation, a less efficient process that does not require oxygen or mitochondria. In fact, many theories suggest that cells which divide a lot decrease the quantity of oxygen their mitochondria consume. It is still unclear what role mitochondria have during phases of intense growth, and if they act differently in cancerous and healthy cells.

Here, Yao et al. use a cell system where division can be turned on or off, and find that when cells quickly multiply, their mitochondria actually consume more oxygen. Further experiments then 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. Yao et al. go on to show that adjusting the fusion process through genetic manipulation helps to control division. When mitochondria cannot combine, cells divide less well; when the compartments can merge more easily, cells multiply faster.

If growing cells do not rely on their mitochondria for their energy demands during multiplication, why do these compartments seem to be essential for division? The reason might be that the mitochondria produce aspartate, a molecule that cells use to replicate.

The work by Yao et al. suggests that at least certain cancer cells may increase their consumption of oxygen to sustain their mitochondria; armed with this knowledge, it may be possible to design new diagnostic tests and new treatments to identify, and potentially target these oxygen-dependent tumor cells.