ROS-induced cytosolic release of mitochondrial PGAM5 accelerates colorectal cancer progression via MST3-mediated YAP activation

Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known to induce neoplastic transformation. However, the precise molecular mechanisms by which mtROS contribute to epithelial tumorigenesis remains only partially understood. Here, we show in colorectal cancer (CRC) models that upon sensing excessive mtROS, the phosphatase PGAM5, which normally localizes in the mitochondria, undergoes aberrant cleavage by presenilin-associated rhomboid-like protein (PARL), and becomes released into the cytoplasm. Cytosolic PGAM5 then directly binds to and dephosphorylates MST3 kinase; this in turn prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and CRC development. Importantly, depletion of MST3 reciprocally promotes accumulation of cytosolic PGAM5 by inducing mitochondrial damage. Taken together, these findings demonstrate that mtROS promotes CRC progression by activating YAP via a novel post-transcriptional positive feedback loop between PGAM5 and MST3, both of which can serve as new targets for the development of novel anti-colon cancer therapeutics.