Human Dopaminergic Neurons Lacking PINK1 Exhibit Disrupted Dopamine Metabolism Related to Vitamin B6 Co-Factors

Abstract

Summary PINK1 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 enzyme m Aconitase, 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.

Mitochondrial Phenotypes in Parkinson’s Diseases—A Focus on Human iPSC-Derived Dopaminergic Neurons

“…This was independently confirmed in Parkin patient iPSC-derived dopamine neurons, with similar phenotypes observed in PINK1 patient neurons as well [ 43 ]. However, no altered mitochondrial morphology was observed in homozygous PINK1 knockout human dopaminergic neurons [ 99 ]. An increase in the numbers of elongated mitochondria in Parkin patient neurons was also reported by Bogetofte and colleagues [ 70 ].…”

“…Similarly, stabilization of endogenous full-length PINK1 and increased ubiquitin phosphorylation was observed [ 149 , 151 ]. Finally, absence of PINK1 in human iPSC-derived dopaminergic neurons leads to inhibition of ionophore-induced mitophagy, providing further evidence for the role of PINK1 in this form of mitophagy [ 99 ].…”

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

“…Research has shown that PINK1 deficiency impairs the differentiation of DA neurons from adult neural stem cells [34] and inhibits the mitophagy and MMP of DA neurons [35]. Knockout of PINK1 affects the neurotransmission of DA neurons and causes motor dysfunction in Drosophila [36].…”

The Role of Supplementation with Natural Compounds in Post-Stroke Patients

“…B vitamins are directly involved in the proper functioning of the nervous system, including cognitive functions. Vitamin B6 (pyridoxine) affects the production of serotonin, dopamine, aminobutyric acid, increases the efficiency of thought processes, prevents apathy and insomnia [ 22 ]. Vitamin B12 (cobalamin) is involved in the formation of the myelin sheath [ 23 ].…”