Mis-localized mitochondrial ribosomes guide ceramide-dependent mitophagy for inducing cell death via alterations of the bioenergetics and metabolism

In this work, we set out experiments to determine the mechanisms that regulate mitochondrial trafficking of p17/PERMIT-CerS1 complex in response to Drp1 activation to induce mitophagy and cellular consequences of this process altering mitochondrial metabolism in cultured cells in situ and genetic mice models in vivo. The data revealed that mislocalized mitochondrial ribosomes on the outer membrane due to Drp1-mediated fission are recognized by p17/PERMIT for CerS1 localization leading to ceramide-dependent mitophagy in response to oxidative stress by the generation of nitric oxide species (NOS). This process then leads to mitochondrial dysfunction resulting in decreased malate/fumarate/aspartate exhaustion, which is restored and prevented by molecular and genetic ablation of p17/PERMIT, LC3, Drp1, and Parkin in cancer cells or patient-derived 2D-organoids or mice brains in response to SoSe or ceramide analog drug, LCL768. Human Head and neck cancer cells have been treated with SoSe or LCL657, total RNA was extracted and loaded on the NanoString nCounter® Human Metabolic Pathways Panel.