Abstract Heart disease is the leading cause of death in the elderly population and the heart is a highly energy-consuming tissue. The high energy requirement is reflected in the abundance of mitochondria in cardiomyocytes and the cristae dense architecture of the organelles. The ATP synthase is well known for its involvement in ATP synthesis, but it also plays an important structural role. This is reflected in its spatiotemporal organisation, making single molecule localisation microscopy in living cells a valuable tool to study ATP synthase under different conditions. In the present study, we studied the effects of cellular senescence on the ATP Synthase in cardiomyocytes. We used human induced pluripotent stem cell derived cardiomyocytes as a model system and induced senescence with low doses of doxorubicin. We observed reduced function of the ATP Synthase while membrane potential was increased, indicating a malfunction of the proton sink. These impairments could however not be related to changes in neither expression nor dimerization levels of the complex. Using single-molecule tracking of ATP synthase, we observed stronger confinement of the enzyme in the cristae. This suggests that the altered spatiotemporal organisation of ATP synthase is linked with impaired ATP production in senescent cardiomyocytes.

Decreased ATP synthase activity is linked to altered spatiotemporal organisation of ATP Synthase in a cellular cardiomyocyte senescent model