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.