title: Altered Mitochondrial Respiration and Other Features of Mitochondrial Function in Parkin-Mutant Fibroblasts from Parkinson's Disease Patients.
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 patient-derived 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.
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: William
authors.identifier: 0000-0002-3946-6663
authors.initials: W
authors.lastname: Haylett
authors.affiliation: Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Chrisna
authors.initials: C
authors.lastname: Swart
authors.affiliation: Centre for Human Metabolomics, Faculty of Natural Sciences, North-West University, Potchefstroom, South Africa.
authors.forename: Francois
authors.initials: F
authors.lastname: van der Westhuizen
authors.affiliation: Centre for Human Metabolomics, Faculty of Natural Sciences, North-West University, Potchefstroom, South Africa.
authors.forename: Hayley
authors.initials: H
authors.lastname: van Dyk
authors.affiliation: Department of Statistics, University of the Western Cape, Cape Town, South Africa.
authors.forename: Lize
authors.initials: L
authors.lastname: van der Merwe
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Celia
authors.initials: C
authors.lastname: van der Merwe
authors.affiliation: Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Ben
authors.initials: B
authors.lastname: Loos
authors.affiliation: Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Carr
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; SA MRC Centre for Tuberculosis Research and the DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.
authors.forename: Craig
authors.initials: C
authors.lastname: Kinnear
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Soraya
authors.initials: S
authors.lastname: Bardien