TY - JOUR
T1 - Mitochondrial membrane potential decrease caused by loss of PINK1 is not due to proton leak, but to respiratory chain defects
AU - Amo, Taku
AU - Sato, Shigeto
AU - Saiki, Shinji
AU - Wolf, Alexander M.
AU - Toyomizu, Masaaki
AU - Gautier, Clement A.
AU - Shen, Jie
AU - Ohta, Shigeo
AU - Hattori, Nobutaka
PY - 2011/1
Y1 - 2011/1
N2 - Mutations in PTEN-induced putative kinase 1 (PINK1) cause a recessive form of Parkinson's disease (PD). PINK1 is associated with mitochondrial quality control and its partial knock-down induces mitochondrial dysfunction including decreased membrane potential and increased vulnerability against mitochondrial toxins, but the exact function of PINK1 in mitochondria has not been investigated using cells with null expression of PINK1. Here, we show that loss of PINK1 caused mitochondrial dysfunction. In PINK1-deficient (PINK1-/-) mouse embryonic fibroblasts (MEFs), mitochondrial membrane potential and cellular ATP levels were decreased compared with those in littermate wild-type MEFs. However, mitochondrial proton leak, which reduces membrane potential in the absence of ATP synthesis, was not altered by loss of PINK1. Instead, activity of the respiratory chain, which produces the membrane potential by oxidizing substrates using oxygen, declined. H2O2 production rate by PINK1-/- mitochondria was lower than PINK1+/+ mitochondria as a consequence of decreased oxygen consumption rate, while the proportion (H2O2 production rate per oxygen consumption rate) was higher. These results suggest that mitochondrial dysfunctions in PD pathogenesis are caused not by proton leak, but by respiratory chain defects.
AB - Mutations in PTEN-induced putative kinase 1 (PINK1) cause a recessive form of Parkinson's disease (PD). PINK1 is associated with mitochondrial quality control and its partial knock-down induces mitochondrial dysfunction including decreased membrane potential and increased vulnerability against mitochondrial toxins, but the exact function of PINK1 in mitochondria has not been investigated using cells with null expression of PINK1. Here, we show that loss of PINK1 caused mitochondrial dysfunction. In PINK1-deficient (PINK1-/-) mouse embryonic fibroblasts (MEFs), mitochondrial membrane potential and cellular ATP levels were decreased compared with those in littermate wild-type MEFs. However, mitochondrial proton leak, which reduces membrane potential in the absence of ATP synthesis, was not altered by loss of PINK1. Instead, activity of the respiratory chain, which produces the membrane potential by oxidizing substrates using oxygen, declined. H2O2 production rate by PINK1-/- mitochondria was lower than PINK1+/+ mitochondria as a consequence of decreased oxygen consumption rate, while the proportion (H2O2 production rate per oxygen consumption rate) was higher. These results suggest that mitochondrial dysfunctions in PD pathogenesis are caused not by proton leak, but by respiratory chain defects.
KW - Membrane potential
KW - Mitochondria
KW - Modular kinetic analysis
KW - Oxidative phosphorylation
KW - PINK1
KW - Parkin
KW - Parkinson's disease
KW - Proton leak
KW - Reactive oxygen species
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UR - http://www.scopus.com/inward/citedby.url?scp=78349309594&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2010.08.027
DO - 10.1016/j.nbd.2010.08.027
M3 - Article
C2 - 20817094
AN - SCOPUS:78349309594
VL - 41
SP - 111
EP - 118
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 1
ER -