Deficiencies in Complex I subunits of the respiratory chain in Parkinson's disease

Mizuno, Yoshikuni; Ohta, Shigeo; Tanaka, Masashi; Takamiya, Shinzaburo; Suzuki, Keiji; Satô, Takeshi; Okumura, Hiroshi; Ozawa, Takayuki; Kagawa, Yasuo

doi:10.1016/0006-291x(89)91141-8

Cited by 707 publications

(354 citation statements)

References 18 publications

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“…Our findings appear to contradict studies showing normal complex I activity in homogenized tissue of the cerebellum, striatum [18,24,25,36] and frontal cortex [18,36] in PD. This difference may be partly due to lower sensitivity of analyses in brain homogenate.…”

Section: Discussioncontrasting

confidence: 99%

“…In the early 1980s, it was discovered that substances inhibiting complex I of the mitochondrial respiratory chain (MRC) cause nigrostriatal degeneration and parkinsonism [6,22,30]. Subsequently, evidence of complex I deficiency was shown in the SNc of individuals with idiopathic PD [25,35]. While this phenomenon has been consistently reproduced by multiple studies [17,18,23,24,34] its significance remains undetermined.…”

Section: Introductionmentioning

confidence: 99%

“…One recent study found that complex I activity was decreased in prefrontal cortex homogenate from individuals with Parkinson's disease dementia (PDD), but within normal range in non-demented PD individuals [14]. Complex I activity measurements and/or Western blot quantification in homogenized samples of the cerebellum and striatum have shown normal findings [18,24,25,36]. Other brain areas remain unexplored.…”

Section: Introductionmentioning

confidence: 99%

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Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

et al. 2017

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Mitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson's disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson's disease and correlate tightly with neuronal mitochondrial DNA damage. To test our hypothesis, we employed a combination of semiquantitative immunohistochemical analyses, Western blot and activity measurements, to assess complex I quantity and function in multiple brain regions from an extensively characterized population-based cohort of idiopathic Parkinson's disease (n = 18) and gender and age matched healthy controls (n = 11). Mitochondrial DNA was assessed in single neurons from the same areas by real-time PCR. Immunohistochemistry showed that neuronal complex I deficiency occurs throughout the Parkinson's disease brain, including areas spared by the neurodegenerative process such as the cerebellum. Activity measurements in brain homogenate confirmed a moderate decrease of complex I function, whereas Western blot was less sensitive, detecting only a mild reduction, which did not reach statistical significance at the group level. With the exception of the substantia nigra, neuronal complex I loss showed no correlation with the load of somatic mitochondrial DNA damage. Interestingly, α-synuclein aggregation was less common in complex I deficient neurons in the substantia nigra. We show that neuronal complex I deficiency is a widespread phenomenon in the Parkinson's disease brain which, contrary to mainstream theory, does not follow the anatomical distribution of neurodegeneration and is not associated with the neuronal load of mitochondrial DNA mutation. Our findings suggest that complex I deficiency in Parkinson's disease can occur independently of mitochondrial DNA damage and may not have a pathogenic role in the neurodegenerative process.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

et al. 2017

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“…Reduced activity level and reduced amount of mitochondrial complex Ｉ have been reported in PD patients [17][18][19][20][21] and in animal models [22,23]. These findings indicate that the function of mitochondrial complex I is related to the onset of PD.…”

Section: Introductionmentioning

confidence: 68%

“…D2 cells are NIH3T3 cells in which the expression of DJ-1 has been knocked down by shRNA targeting the mouse DJ-1 gene as described previously [17]. HL-60 cells were cultured in RPMI1640 medium with 10% fetal calf serum.…”

Section: Cell Culturementioning

confidence: 99%

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

Hayashi

Ishimori

Takahashi-Niki

et al. 2009

Biochemical and Biophysical Research Communications

170

119

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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.

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