Regulation of intracellular energy supplies by cell cycle kinetics using a single cell approach.

Both proliferative and anti-proliferative pathways are induced after acute kidney injury. The consequences of proliferation on energy homeostasis and cell viability are unknown. We hypothesized that proliferation regulation is an important determinant of epithelial fate after acute kidney injury. We studied the relationship between proliferation and cell viability in kidney tubular cells. We then analyzed the effect of proliferation on the intracellular ATP/ADP ratio. Finally, we used transcriptomic data from transplanted kidneys to study the relationship between cell proliferation and energy production with different clinical evolutions. We found that proliferation is associated with decreased survival after toxic or energetic stresses in kidney proximal tubular cells. In vitro, we found that the ATP/ADP ratio oscillates reproducibly throughout the cell cycle, and that proliferation is instrumental to an overall decrease in intracellular ATP/ADP ratio. In vivo, in injured kidneys, we found that proliferation was strongly associated with a specific decrease in the expression of the mitochondria-encoded genes of the oxidative phosphorylation pathway as opposed to the nucleus-encoded ones. These observations suggest that mitochondrial function is the limiting factor for energy production in kidney cells proliferating after injury. The association of increased proliferation and decreased mitochondrial function was associated with poor renal outcomes. In summary, we show that proliferation is an energy demanding process impairing the cellular ability to cope with a toxic or ischemic injury, identifying the association of proliferative repair and metabolic recovery as indispensable and interdependent features for successful kidney repair. One Sentence SummaryProliferation decreases energy availability in kidney epithelial cells and is associated with enhanced cell death and chronic kidney disease in case of a superimposed metabolic stress.