Mitochondrial-cell cycle cross-talk drives endoreplication in heart disease

In response to stress, cardiomyocytes reduce their mitochondrial metabolism and undergo hypertrophy. Before increasing in size, cells can duplicate their genetic material without dividing, a process called endoreplication. Here, Bischof et al. studied the mechanism underlying changes to metabolism and growth in hypertrophic cardiomyopathy. They found that ATP5A1, a subunit of ATP synthase, was repressed in cardiac hypertrophy. In cardiomyocytes or mice, inactivating Atp5a1 reduced ATP, increased ADP, activated AMPK, and increased ploidy of cardiomyocytes and cardiomyocyte hypertrophy. MTHFD1L, a mitochondrial enzyme, was identified as a driver of endoreplication, and mice deficient in Mthfd1l and Atp5a1 were protected from pressure overload–induced cardiac hypertrophy. This study elucidates the pathway by which mitochondrial ADP can contribute to pathologic cardiac growth.