The Influence of Cellular Redox State on Mitosis

Abstract

To divide, cell cycle machinery must be tightly regulated. This is done through a complex and dynamic network of well-characterized protein kinases, ensuring cells only transition to subsequent cell cycle stages when specific checkpoints have been passed. This regulation prevents cells with insufficient biomass, incomplete DNA replication, or misaligned chromosomes from dividing into two daughter cells. Here, we show direct regulation of the key mitotic regulator, Aurora kinase B, by changes in mitochondrial metabolism during mitosis. In early mitosis, an increase in mitochondrial membrane potential coincides with a robust reduction in cellular redox status, preventing disulfide bond-mediated activation of Aurora kinase B as a determinant of anaphase onset. In cells lacking the ability to alter their redox state due to deficient mitochondrial respiratory function, deficient Aurora kinase B activity leads to mitotic abnormalities and death. This work identifies a novel mechanism by which cellular metabolism regulates cell cycle progression and has important impacts for human diseases such as cancer, as errors in cell division are directly linked to aberrant proliferation.