摘要：SummaryPINK1 loss-of-function mutations cause early onset Parkinson disease. PINK1-Parkin mediated mitophagy has been well studied, but the relevance of the endogenous process in the brain is debated.Here, the absence of PINK1 in human dopaminergic neurons inhibits ionophore-induced mitophagy and reduces mitochondrial membrane potential. Compensatory, mitochondrial renewal maintains mitochondrial morphology and protects the respiratory chain. This is paralleled by metabolic changes, including inhibition of the TCA cycle enzymemAconitase, accumulation of NAD+, and metabolite depletion. Loss of PINK1 disrupts dopamine metabolism by critically affecting its synthesis and uptake. The mechanism involves steering of key amino acids toward energy production rather than neurotransmitter metabolism and involves cofactors related to the vitamin B6 salvage pathway identified using unbiased multi-omics approaches.We propose that reduction of mitochondrial membrane potential that cannot be controlled by PINK1 signaling initiates metabolic compensation that has neurometabolic consequences relevant to Parkinson disease.Graphical AbstractDisplay OmittedHighlights•PINK1 KO hDANs do not undergo ionophore-induced mitophagy yet CI remains active•PINK1 KO impacts the TCA cycle viamAconitase leading to depletion of key amino acids•PINK1 KO silencesPNPO,which provides essential biological co-factors•Dopamine pools and neurotransmitter uptake are reduced by PINK1 loss of functionMolecular Biology; Molecular Neuroscience; Stem Cells Research; Omics
