Link between mitochondrial hyperfusion and genome stability

Mitochondria constantly undergo fusion and fission events that are integrated with the cell cycle. Mitochondrial remodeling throughout the cell cycle is thought to help meet the varying cellular energy demands of the cell and to ensure faithful inheritance of mitochondria during cell division. Dynamin-related protein 1 (Drp1) is essential for mitochondrial fission, and Drp1 deficiency results in a failure of mitophagy – the removal of damaged mitochondria – leading to ATP depletion and, ultimately, proliferation defects. However, some data suggest that Drp1 also has other effects on proliferation, which are independent of the mitochondrial energy metabolism. On page 5745, Bennett Van Houten and colleagues set out to investigate the molecular mechanisms that link mitochondrial dynamics to the cell cycle. They show that RNAi-mediated loss of Drp1 results in mitochondrial hyperfusion and, surprisingly, arrest of cells in G2/M phase of the cell cycle and in aneuploidy. Addressing the underlying basis of this arrest, they uncovered an untimely expression of cyclin E and the subsequent replication stress activating the G2/M checkpoint through Ataxia telangiectasia mutated (ATM) kinase to be the cause, and not defects in the generation of mitochondrial ATP. Taken together, their data indicate that genome instability that is associated with mitochondrial dysfunction and mediated by Drp1 has a different mechanistic basis, which is unrelated to mitochondrial energy metabolism.