Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency.
Energy production via the mitochondrial electron transport chain (ETC) and mitophagy are two important processes affected in Parkinson's disease (PD). Interestingly, PINK1, mutations of which cause early-onset PD, plays a key role in both processes, suggesting that these two mechanisms are connected. However, the converging link of both pathways currently remains enigmatic. Recent findings demonstrated that lipid aggregation, along with defective mitochondria, is present in postmortem brains of PD patients. In addition, an increasing body of evidence shows that sphingolipids, including ceramide, are altered in PD, supporting the importance of lipids in the pathophysiology of PD. Here, we identified ceramide to play a crucial role in PINK1-related PD that was previously linked almost exclusively to mitochondrial dysfunction. We found ceramide to accumulate in mitochondria and to negatively affect mitochondrial function, most notably the ETC. Lowering ceramide levels improved mitochondrial phenotypes in pink1-mutant flies and PINK1-deficient patient-derived fibroblasts, showing that the effects of ceramide are evolutionarily conserved. In addition, ceramide accumulation provoked ceramide-induced mitophagy upon PINK1 deficiency. As a result of the ceramide accumulation, β-oxidation in PINK1 mutants was decreased, which was rescued by lowering ceramide levels. Furthermore, stimulation of β-oxidation was sufficient to rescue PINK1-deficient phenotypes. In conclusion, we discovered a cellular mechanism resulting from PD-causing loss of PINK1 and found a protective role of β-oxidation in ETC dysfunction, thus linking lipids and mitochondria in the pathophysiology of PINK1-related PD. Furthermore, our data nominate β-oxidation and ceramide as therapeutic targets for PD.
['Vos|Melissa|M|0000-0002-9883-7698', 'Dulovic-Mahlow|Marija|M|', 'Mandik|Frida|F|', 'Frese|Lisa|L|0000-0002-7105-7069', 'Kanana|Yuliia|Y|0000-0002-0838-9714', 'Haissatou Diaw|Sokhna|S|0000-0002-0424-3777', 'Depperschmidt|Julia|J|0000-0002-2402-3579', 'Böhm|Claudia|C|0000-0002-5446-464X', 'Rohr|Jonas|J|', 'Lohnau|Thora|T|', 'König|Inke R|IR|', 'Klein|Christine|C|0000-0003-2102-3431']
ceramide β-oxidation PINK1 mitochondria Parkinson’s disease