In:
European Journal of Neuroscience, Wiley, Vol. 45, No. 4 ( 2017-02), p. 528-535
Abstract:
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 .
Type of Medium:
Online Resource
ISSN:
0953-816X
,
1460-9568
DOI:
10.1111/ejn.2017.45.issue-4
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2005178-5
SSG:
12