Mitochondrial respiratory failure in skeletal muscle from patients with Parkinson's disease and multiple system atrophy

Blin, Olivier; Desnuelle, Claude; Rascol, Olivier; Borg, M.; Paul, H; Azulay, Jean‐Philippe; Bille, F.; Figarella, Dominique; Coulom, F; Pellissier, Jean‐François; Montastruc, Jean‐Louis; Chatel, M.; Serratrice, G

doi:10.1016/0022-510x(94)90248-8

Cited by 168 publications

(109 citation statements)

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“…Individuals are likely to be variably exposed to numerous natural or synthetic complex I inhibitors through diet, drinking water or other environmental factors. Such exposures, combined with genetic differences in complex I function [14][15][16][17][18][19][20][21][22] , or inter-individual differences in the ability to metabolize xenobiotics 7 , may underlie most cases of typical idiopathic PD.…”

Section: Discussionmentioning

confidence: 99%

“…The selectivity of MPP + for dopaminergic neurons is due to the fact that it is an excellent substrate for the dopamine transporter, and is thereby accumulated preferentially in cells that transport dopamine 13 . Following recognition of MPTP's toxicity and its mechanism of action, several laboratories reported a selective defect in complex I of the electron transport chain in PD [14][15][16][17][18][19][20][21][22] . This defect seems to be systemic, affecting not only the brain, but also peripheral tissues such as platelets.…”

Section: Articlesmentioning

confidence: 99%

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Chronic systemic pesticide exposure reproduces features of Parkinson's disease

et al. 2000

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articlesParkinson's disease is a late-onset, progressive motor disease marked by selective degeneration of dopaminergic neurons of the substantia nigra and formation of fibrillar cytoplasmic inclusions, known as Lewy bodies, which contain ubiquitin and α-synuclein 1 . Rare cases of familial PD have been linked to mutations in α-synuclein or parkin [2][3][4] , but the cause of the more commonly encountered sporadic disease is unknown, and the role of genetics in these cases is uncertain 5 . Post mortem studies strongly implicate oxidative damage and mitochondrial impairment in the pathogenesis of PD 6 . Epidemiological studies have suggested that pesticide exposure is associated with an increased risk of developing PD 7-9 .After the pro-toxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was reported to produce in humans an acute parkinsonian syndrome that is virtually indistinguishable from idiopathic PD 10 , its metabolite, 1-methyl-4-pyridinium (MPP + ), was found to be a mitochondrial poison that inhibits mitochondrial respiration at complex I of the electron transport chain 11,12 . The selectivity of MPP + for dopaminergic neurons is due to the fact that it is an excellent substrate for the dopamine transporter, and is thereby accumulated preferentially in cells that transport dopamine 13 . Following recognition of MPTP's toxicity and its mechanism of action, several laboratories reported a selective defect in complex I of the electron transport chain in PD [14][15][16][17][18][19][20][21][22] . This defect seems to be systemic, affecting not only the brain, but also peripheral tissues such as platelets.An accurate in vivo experimental model of PD should reproduce the progressive, selective nigrostriatal dopaminergic degeneration and Lewy body formation seen in PD, test the relevance of the systemic complex I defect, and explain the potential involvement of pesticide exposure in development of parkinsonism. Unfortunately, no current animal model incorporates all of these features. The MPTP model causes selective nigrostriatal degeneration by inhibiting complex I, but, unlike PD, MPTP does not cause a systemic complex I defect. Instead, the inhibition is highly selective for dopaminergic neurons. Moreover, MPTP does not typically produce cytoplasmic inclusions that closely resemble Lewy bodies 23 . Transgenic mice expressing the pathogenic human α-synuclein mutation develop modest dopaminergic pathology (although the specificity of this degeneration is not detailed), and many neurons contain small cytoplasmic inclusions that are granular rather than fibrillar 24 .To develop a more accurate in vivo model of PD, we exposed rats chronically, continuously and systemically to the common pesticide, rotenone. A naturally occurring compound derived from the roots of certain plant species, rotenone is commonly used as an insecticide in vegetable gardens, and is also used to kill or sample fish populations in lakes and reservoirs. It is widely believed to be a safe, natural alternative to synthetic pesticides. Ro...

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Section: Discussionmentioning

confidence: 99%

Section: Articlesmentioning

confidence: 99%

Chronic systemic pesticide exposure reproduces features of Parkinson's disease

et al. 2000

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“…Some studies reported that complex I deficiency is only observed in the substantia nigra [16][17][18] or is more severe in nigral neuronal mitochondria than in platelet mitochondria [19]. Other studies report complex I abnormalities in mitochondria isolated from muscle [5,20,21], platelets [4,[22][23][24][25], the striatum [3], lymphocytes [23,26], cortical brain tissues [27], and fibroblasts [28] of human PD patients. Changes in subunit proteins or function of complex II, III, IV, and V have also been reported in PD [3,5,25,27,29,30], but these changes are less consistently observed and could be secondary to other factors.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Dysfunction in Parkinson's Disease

Zhu

Chu

2010

JAD

120

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Abstract. It is clear from a striking convergence of human tissue studies, neurotoxin models, and genetic models that mitochondrial dysregulation plays a central pathogenic role in Parkinson's disease (PD) and related neurodegenerative conditions. Impaired mitochondrial quality could result from both increased damage and decreased ability to repair or clear damaged mitochondria. In particular, common deficits in mitochondrial respiratory chain function, oxidative stress, morphology/dynamics, and calcium handling capacities have been described in multiple PD model systems employing complex I inhibitors, 6-hydroxydopamine and molecular manipulation of Parkinsonian genes including α-synuclein, PTEN-induced kinase 1, Parkin, DJ-1, and, to a lesser extent, leucine rich repeat kinase 2. The most recent and exciting work implicates alterations in the regulation of macroautophagy and likely of selective mitophagic clearance of damaged mitochondria, although additional studies are needed to resolve some issues in this area. Future studies emphasizing the normal mitoprotective function(s) of proteins associated with recessive loss-of-function causes of familial PD, as well as compensatory mechanisms operating in their absence, may offer particularly valuable insights into strategies to enhance mitochondrial health.

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“…Two decades later, the controversy over the anatomic distribution of the PD complex I defect seems to have been settled (128,131). It has repeatedly been demonstrated in PD subject platelets and muscle, and has also been demonstrated in fibroblasts and lymphocytes (7,9,12,13,18,34,42,65,85,87,94,119,162). More recently, it was shown that the original controversy likely arose entirely as a consequence of methodological issues (128) (Fig.…”

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confidence: 99%

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

Swerdlow

2012

Antioxidants & Redox Signaling

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Significance: Mitochondria are currently believed to play an important role in the neurodysfunction and neurodegeneration that underlie Parkinson's disease (PD). Recent Advances: While it increasingly appears that mitochondrial dysfunction in PD can have different causes, it has been proposed that mitochondrial DNA (mtDNA) may account for or drive mitochondrial dysfunction in the majority of the cases. If correct, the responsible mtDNA signatures could represent acquired mutations, inherited mutations, or population-distributed polymorphisms. Critical Issues and Future Directions: This review discusses the case for mtDNA as a key mediator of PD, and especially focuses on data from studies of PD cytoplasmic hybrid (cybrid) cell lines. Antioxid. Redox Signal. 16, 950-964.

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Mitochondrial respiratory failure in skeletal muscle from patients with Parkinson's disease and multiple system atrophy

Cited by 168 publications

References 39 publications

Chronic systemic pesticide exposure reproduces features of Parkinson's disease

Chronic systemic pesticide exposure reproduces features of Parkinson's disease

Mitochondrial Dysfunction in Parkinson's Disease

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

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