Inhibition of the mitochondrial calcium uniporter rescues dopaminergic neurons in pink1−/− zebrafish Article Swipe
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· 2016
· Open Access
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· DOI: https://doi.org/10.1111/ejn.13473
· OA: W2555397029
Mutations in PTEN ‐induced putative kinase 1 ( PINK 1 ) are a cause of early onset Parkinson's disease ( PD ). Loss of PINK 1 function causes dysregulation of mitochondrial calcium homeostasis, resulting in mitochondrial dysfunction and neuronal cell death. We report that both genetic and pharmacological inactivation of the mitochondrial calcium uniporter ( MCU ), located in the inner mitochondrial membrane, prevents dopaminergic neuronal cell loss in pink1 Y431 * mutant zebrafish ( Danio rerio ) via rescue of mitochondrial respiratory chain function. In contrast, genetic inactivation of the voltage dependent anion channel 1 ( VDAC 1), located in the outer mitochondrial membrane, did not rescue dopaminergic neurons in PINK 1 deficient D. rerio . Subsequent gene expression studies revealed specific upregulation of the mcu regulator micu1 in pink1 Y431 * mutant zebrafish larvae and inactivation of micu1 also results in rescue of dopaminergic neurons. The functional consequences of PINK 1 deficiency and modified MCU activity were confirmed using a dynamic in silico model of Ca 2+ triggered mitochondrial activity. Our data suggest modulation of MCU ‐mediated mitochondrial calcium homeostasis as a possible neuroprotective strategy in PINK 1 mutant PD .
