DJ-1 binds to mitochondrial complex I and maintains its activity

Abstract

Parkinson's disease (PD) is caused by neuronal cell death, and oxidative stress and mitochondrial dysfunction are thought to be responsible for onset of PD. DJ-1, a causative gene product of a familial form of Parkinson's disease, PARK7, plays roles in transcriptional regulation and anti-oxidative stress. The possible mitochondrial function of DJ-1 has been proposed, but its exact function remains unclear. In this study, we found that DJ-1 directly bound to NDUFA4 and ND1, nuclear and mitochondrial DNA-encoding subunits of mitochondrial complex I, respectively, and was co-localized with complex I and that complex I activity was reduced in DJ-1-knockdown NIH3T3 and HEK293cells. These findings suggest that DJ-1 is an integral mitochondrial protein and that DJ-1 plays a role in maintenance of mitochondrial complex I activity.

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Lev et al(2008) [272] described a cellular redistribution of DJͲ1 in cells exposed to neurotoxins. This work was extended by Hayashi et al(2009) [281], who showed DJͲ1 binding to NADH dehydrogenase (ubiquinone) 1 ɲͲ subcomplex 4 (NDUFA4) and to mitochondrial encoded NADH dehydrogenase 1 (ND1), nuclear and mitochondrial DNAͲencoding subunits of complex I, respectively, validating the importance of DJͲ1 in mitochondrial function. Recently, a direct link between loss of DJͲ1, impaired mitochondrial stress response and reduced clearance of mitochondria by lysosomal degradation was described [282].…”

Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Lev et al [272] described a cellular redistribution of DJ-1 in cells exposed to neurotoxins. This work was extended by Hayashi et al [281], who showed DJ-1 binding to NADH dehydrogenase (ubiquinone) 1a-subcomplex 4 and to mitochondrial-encoded NADH dehydrogenase 1, nuclear and mitochondrial DNA-encoding subunits of complex I, respectively, validating the importance of DJ-1 in mitochondrial function. Recently, a direct link between loss of DJ-1, impaired mitochondrial stress response, and reduced clearance of mitochondria by lysosomal degradation was described [282].…”

Common Mechanisms of Onset of Cancer and Neurodegenerative Diseases

“…47) DJ-1 is localized in the cytoplasm, nucleus and mitochondria 26,48) and is secreted into culture medium [49][50][51] or serum, [52][53][54][55][56][57][58][59] cerebrospinal fluid, 53,54,60) saliva 61,62) and nipple fluid. 63) DJ-1 is translocated from the cytoplasm to nucleus upon addition of a mitogen to the culture medium 26) and is translocated to mitochondria after oxidative stress.…”

“…DJ-1 is a multi-functional protein, [118][119][120] having functions in transcriptional regulation, [121][122][123][124][125][126][127][128][129][130][131][132][133][134][135] anti-oxidative stress reaction, 64,112,113,136,137) mitochondrial regulation, 48,[138][139][140][141][142][143][144][145][146] regulation of signal transduction, 96,123,132,[147][148][149][150][151][152] and functions as a protease, 58,[153][154][155] a chaperone 156,157) and a deglycase 158) (Fig. 5).…”

“…48,64,145) Mitochondria with abnormal morphology such as fragmented mitochondria and with reduced mitochondrial membrane potential are observed in DJ-1-knockout mice. 142,143) We have found that DJ-1 binds to subunits of mitochondrial complex I in respiration complexes, enhances its activity, and is co-localized with mitochondrial complex I in the mitochondrial inner membrane.…”