Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency
Melissa Vos, Marija Dulovic‐Mahlow, Frida Mandik, Lisa Frese, Yuliia Kanana, Sokhna Haissatou Diaw, Julia Depperschmidt, Claudia Böhm, Jonas Rohr, Thora Lohnau, Inke R. König, Christine Klein
Abstract
Significance Ceramide accumulates in Parkinson’s disease–related PINK1 deficiency to initiate ceramide-mediated mitophagy as an alternative pathway to overcome defective PINK1-related mitophagy and the concomitant increased requirements for mitochondrial clearance. Increased ceramide levels negatively correlate with β-oxidation and thus decrease efficiency of the electron transport chain, further increasing the need for mitochondrial clearance. Interfering with this vicious cycle can constitute a novel therapeutic strategy as suggested by our data showing that a reduction of ceramide levels or stimulation of β-oxidation improve the PINK1 -mutant phenotypes.