RIPK1-Dependent Mitophagy: A Novel Mechanism to Eliminate ECM-Detached Cells

For cancer cells to survive during extracellular matrix (ECM) detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to reactive oxygen species (ROS) generation, although the mechanistic underpinnings of this link remain ill defined. Here, we uncover a role for receptor-interacting protein kinase 1 (RIPK1) in the modulation of mitochondrial ROS levels and cell viability during ECM detachment. Mechanistically, we find that RIPK1 activation during ECM detachment results in the induction of mitophagy through a mechanism requiring the mitochondrial phosphatase phosphoglycerate mutase family member 5 (PGAM5). As a consequence of mitophagy induction, ECM-detached cells experience diminished isocitrate dehydrogenase 2 (IDH2)-mediated nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) production in the mitochondria and the subsequent elevation in mitochondrial ROS levels leads to non-apoptotic cell death. Furthermore, we find that antagonizing RIPK1 or PGAM5 enhances tumor formation in vivo. Expanding upon these studies further, we also find that prostate cancer cell lines that have developed resistance to the immune checkpoint blockade inhibitor PD-1 have antagonized the liability associated with RIPK1/PGAM5-dependent mitophagy to enhance survival during ECM detachment. In aggregate, RIPK1-mediated induction of mitophagy may be an efficacious target for therapeutics aimed at eliminating ECM-detached cancer cells.