LAUSR

Significance Sustained energy stress and cellular dysfunction can cause excessive mitochondrial fragmentation, a feature observed in metabolic diseases, cancer, cardiovascular and neurological disorders, as well as in diseases associated with mitochondrial DNA mutations. We now show that pyruvate dehydrogenase kinase 4 (PDK4), plays a role in the regulation of mitochondrial dynamics. PDK4 promotes mitochondrial fission via phosphorylation of Septin 2 (SEPT2) at Ser218 and thereby triggering the recruitment of DRP1 to the mitochondria. A high level of PDK4 protein expression and SEPT2 phosphorylation was also found to be associated with lung adenocarcinoma patients with extensive mitochondrial damage. Our findings provide a mechanistic understanding that PDK4 can affect mitochondrial dynamics and cellular respiratory status under energy stress conditions.