Altered Mitochondrial Respiration and Other Features of Mitochondrial Function inParkin-Mutant Fibroblasts from Parkinson’s Disease Patients

Mutations in theparkingene 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 withparkinnull mutations are particularly valuable for investigating the mitochondrial functions of parkin. However, published results reporting on patient-derivedparkin-mutant fibroblasts have been inconsistent. This study aimed to functionally compareparkin-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 inparkinand 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 theparkin-mutant fibroblasts compared to control fibroblasts (p= 0.0093), while exhibiting more fragmented mitochondrial networks (p=0.0304). Moreover, cell growth of theparkin-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.