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Cerebral mitochondrial electron transport chain dysfunction in multiple system atrophy and Parkinson's disease.

ABSTRACT: Multiple system atrophy (MSA) is a neurodegenerative disease characterised by glial cytoplasmic inclusions (GCIs), containing ?-synuclein. Mutated COQ2, encoding an enzyme essential for co-enzyme Q10 (CoQ10) biosynthesis, has been associated with MSA. CoQ10 is an electron carrier in the mitochondrial electron transport chain (ETC) and antioxidant. It has been shown to be deficient in MSA brain tissue, thus implicating mitochondrial dysfunction in MSA. To investigate mitochondrial dysfunction in MSA further we examined ETC activity in MSA and control brain tissue, compared with Parkinson's disease (PD) where mitochondrial dysfunction is known to be important. Using cerebellar and occipital white matter ETC complex I, II/III and IV activities were measured spectrophotometrically, selected individual components of the ETC were assessed by immunoblotting and cellular complex IV activity was analysed by enzyme histochemistry. We show decreased complex II/III activity with increased complex I and IV activity in MSA cerebellar white matter. This corresponds with the deficit in CoQ10 previously described in MSA and reflects the high regional pathological burden of GCIs. This study highlights mitochondrial dysfunction in MSA pathogenesis, suggests an influence on selective regional vulnerability to disease and points to shared disease mechanisms in ?-synucleinopathies.

SUBMITTER: Foti SC

PROVIDER: S-EPMC6484105 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Cerebral mitochondrial electron transport chain dysfunction in multiple system atrophy and Parkinson's disease.

Foti Sandrine C SC Hargreaves Iain I Carrington Stephanie S Kiely Aoife P AP Houlden Henry H Holton Janice L JL

Scientific reports 20190425 1

Multiple system atrophy (MSA) is a neurodegenerative disease characterised by glial cytoplasmic inclusions (GCIs), containing α-synuclein. Mutated COQ2, encoding an enzyme essential for co-enzyme Q10 (CoQ10) biosynthesis, has been associated with MSA. CoQ10 is an electron carrier in the mitochondrial electron transport chain (ETC) and antioxidant. It has been shown to be deficient in MSA brain tissue, thus implicating mitochondrial dysfunction in MSA. To investigate mitochondrial dysfunction in ...[more]

PMID: 31024027

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Project description:Prior studies have shown that disruption of mitochondrial electron transport chain (ETC) function in the nematode Caenorhabditis elegans can result in life extension. Counter to these findings, many mutations that disrupt ETC function in humans are known to be pathologically life-shortening. In this study, we have undertaken the first formal investigation of the role of partial mitochondrial ETC inhibition and its contribution to the life-extension phenotype of C. elegans. We have developed a novel RNA interference (RNAi) dilution strategy to incrementally reduce the expression level of five genes encoding mitochondrial proteins in C. elegans: atp-3, nuo-2, isp-1, cco-1, and frataxin (frh-1). We observed that each RNAi treatment led to marked alterations in multiple ETC components. Using this dilution technique, we observed a consistent, three-phase lifespan response to increasingly greater inhibition by RNAi: at low levels of inhibition, there was no response, then as inhibition increased, lifespan responded by monotonically lengthening. Finally, at the highest levels of RNAi inhibition, lifespan began to shorten. Indirect measurements of whole-animal oxidative stress showed no correlation with life extension. Instead, larval development, fertility, and adult size all became coordinately affected at the same point at which lifespan began to increase. We show that a specific signal, initiated during the L3/L4 larval stage of development, is sufficient for initiating mitochondrial dysfunction-dependent life extension in C. elegans. This stage of development is characterized by the last somatic cell divisions normally undertaken by C. elegans and also by massive mitochondrial DNA expansion. The coordinate effects of mitochondrial dysfunction on several cell cycle-dependent phenotypes, coupled with recent findings directly linking cell cycle progression with mitochondrial activity in C. elegans, lead us to propose that cell cycle checkpoint control plays a key role in specifying longevity of mitochondrial mutants.

Dataset Information

Cerebral mitochondrial electron transport chain dysfunction in multiple system atrophy and Parkinson's disease.

Publications

Cerebral mitochondrial electron transport chain dysfunction in multiple system atrophy and Parkinson's disease.

Similar Datasets

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