Parkin is not required to sustain OXPHOS function in adult mammalian tissues

Abstract

Loss-of-function variants in thePRKNgene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson’s disease (PD). Extensivein vitroandin vivostudies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditionalParkinknockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development ofParkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygousPRKNpathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.

PINK1 regulated basal mitophagy is evident in skeletal muscles

“…It is also likely that tissues accumulate mutations at different rates with the POLG D257A mutation and could possibly contribute to the heterogeneity of effects encountered in different organs. However, two recent publications have also failed to identify a neurodegenerative phenotype when the PINK1/Parkin pathway is lost in the background of the mutator mouse [28,29]. More work is obviously needed to determine the interaction of these pathways.…”

Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice

“…Though ventricular mitochondria were not significantly impaired by loss of mtDNA fidelity, loss of Parkin improved electron flow efficiency beyond WT levels. Traditionally, loss of Parkin is thought to promote increased mitochondrial dysfunction [39,41,68]; however, numerous recent reports, including our study, contest this [36,42,[69][70][71]. Previously, our lab reported rats lacking Parkin do not exhibit functional deficits in striatal synaptic mitochondria [72].…”