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Altered Mitochondrial Respiration and other Features of Mitochondrial Function in Parkin-Mutant Fibroblasts from Parkinson’s Disease Patients


Affiliations
1 Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa
2 Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
3 Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa
4 Department of Statistics, University of the Western Cape, Cape Town, South Africa
5 Division of Neurology, Stellenbosch University, Cape Town, South Africa
 

Mutations in the parkin gene are the most common cause of early-onset Parkinson’s disease (PD). Parkin, an E3 ubiquitin ligase, is involved in respiratory chain function, mitophagy, and mitochondrial dynamics. Human cellular models with parkin null mutations are particularly valuable for investigating the mitochondrial functions of parkin. However, published results reporting on patientderived parkin-mutant fibroblasts have been inconsistent. This study aimed to functionally compare parkin-mutant fibroblasts from PD patients with wild-type control fibroblasts using a variety of assays to gain a better understanding of the role of mitochondrial dysfunction in PD. To this end, dermal fibroblasts were obtained from three PD patients with homozygous whole exon deletions in parkin and three unaffected controls. Assays of mitochondrial respiration, mitochondrial network integrity, mitochondrial membrane potential, and cell growth were performed as informative markers of mitochondrial function. Surprisingly, it was found that mitochondrial respiratory rates were markedly higher in the parkin-mutant fibroblasts compared to control fibroblasts (p = 0.0093), while exhibiting more fragmented mitochondrial networks (p = 0.0304). Moreover, cell growth of the parkin-mutant fibroblasts was significantly higher than that of controls (p = 0.0001). These unanticipated findings are suggestive of a compensatory mechanism to preserve mitochondrial function and quality control in the absence of parkin in fibroblasts, which warrants further investigation.
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  • Altered Mitochondrial Respiration and other Features of Mitochondrial Function in Parkin-Mutant Fibroblasts from Parkinson’s Disease Patients

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Authors

William Haylett
Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa
Chrisna Swart
Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
Francois van der Westhuizen
Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa
Hayley van Dyk
Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa
Lize van der Merwe
Department of Statistics, University of the Western Cape, Cape Town, South Africa
Celia van der Merwe
Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa
Ben Loos
Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
Jonathan Carr
Division of Neurology, Stellenbosch University, Cape Town, South Africa
Craig Kinnear
Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa
Soraya Bardien
Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa

Abstract


Mutations in the parkin gene are the most common cause of early-onset Parkinson’s disease (PD). Parkin, an E3 ubiquitin ligase, is involved in respiratory chain function, mitophagy, and mitochondrial dynamics. Human cellular models with parkin null mutations are particularly valuable for investigating the mitochondrial functions of parkin. However, published results reporting on patientderived parkin-mutant fibroblasts have been inconsistent. This study aimed to functionally compare parkin-mutant fibroblasts from PD patients with wild-type control fibroblasts using a variety of assays to gain a better understanding of the role of mitochondrial dysfunction in PD. To this end, dermal fibroblasts were obtained from three PD patients with homozygous whole exon deletions in parkin and three unaffected controls. Assays of mitochondrial respiration, mitochondrial network integrity, mitochondrial membrane potential, and cell growth were performed as informative markers of mitochondrial function. Surprisingly, it was found that mitochondrial respiratory rates were markedly higher in the parkin-mutant fibroblasts compared to control fibroblasts (p = 0.0093), while exhibiting more fragmented mitochondrial networks (p = 0.0304). Moreover, cell growth of the parkin-mutant fibroblasts was significantly higher than that of controls (p = 0.0001). These unanticipated findings are suggestive of a compensatory mechanism to preserve mitochondrial function and quality control in the absence of parkin in fibroblasts, which warrants further investigation.