Inhibition of the mitochondrial calcium uniporter rescues dopaminergic neurons in pink1 pink1 ? / ? ? ? / ? ? zebrafish

摘要

Abstract Mutations inPTEN induced putative kinase 1(PINK 1) are a cause of early onset Parkinson's disease (PD ). Loss ofPINK 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 inpink1 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 inPINK 1 deficientD.爎erio . Subsequent gene expression studies revealed specific upregulation of themcu regulatormicu1 inpink1 Y431 * mutant zebrafish larvae and inactivation of micu1 also results in rescue of dopaminergic neurons. The functional consequences ofPINK 1 deficiency and modifiedMCU activity were confirmed using a dynamicin silico model of Ca2+ triggered mitochondrial activity. Our data suggest modulation ofMCU mediated mitochondrial calcium homeostasis as a possible neuroprotective strategy inPINK 1 mutantPD .