pyruvate dehydrogenase kinase 4 regulate mitochondrial dynamics

Mitochondrial dynamics provides cells with the flexibility required to adapt and respond to mitochondrial toxins, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here we show that pyruvate dehydrogenase kinase 4 (PDK4) is required for cells to undergo rapid mitochondrial fragmentation when challenged with toxins. Moreover, PDK4 overexpression was sufficient to promote mitochondrial fission even in the absence of stress. Phosphoproteomic screen for PDK4 substrates identified cytoplasmic GTPase, Septin 2 (SEPT2), as the key effector molecule that acts as a receptor for DRP1 to promote mitochondrial fission. PDK4-mediated mitochondrial reshaping limits mitochondrial bioenergetics, supports cancer cell growth and revealed PDK4-SEPT2-DRP1 axis as a regulator of mitochondrial dynamics at the interface between cellular bioenergetics and mitochondrial dynamics