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

ABSTRACT: Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson’s disease (PD). Extensive in vitro and in vivo studies 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 conditional Parkin knockout 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 of Parkin-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 heterozygous PRKN pathogenic 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE263057 | GEO | 2024/04/03

REPOSITORIES: GEO

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Project description:Mutations in the E3 ubiquitin ligase Parkin cause autosomal recessive Parkinson’s disease. In concert with PINK1, Parkin regulates the clearance of dysfunctional mitochondria via lysosomes. In response, new mitochondria are generated through an interplay of nuclear- and mitochondrial-encoded proteins. Mouse and overexpression models suggests that Parkin also influences these processes, both in the nuclear cascade and at the level of the mitochondrial genome. Additionally, Parkin has been shown to prevent mitochondrial membrane permeation, impeding the escape of mitochondrial DNA (mtDNA). In line with this, serum from Parkin mutation carriers showed higher levels of circulating cell-free mtDNA (ccf-mtDNA) and inflammatory cytokines – a result of the innate immune response - which can be triggered by cytosolic mtDNA. However, Parkin’s relationship with the mitochondrial genome and the mitogenesis pathway has not been explored in patient-derived neurons. To investigate this aspect of Parkin’s cellular function endogenously, we generated induced pluripotent stem cell (iPSC)-derived midbrain neurons from Parkin mutation carriers and healthy controls. In Parkin-deficient cells, several factors in the mitochondrial biogenesis pathway were significantly reduced, resulting in impaired mtDNA homeostasis - a phenomenon that was exacerbated in dopaminergic neurons. Moreover, in response to a lack of freely accessible NAD+, the energy sensor Sirtuin 1, which simultaneously controls mtDNA maintenance processes and mitophagy, was downregulated in Parkin-deficient neurons. However, while impaired lysosomal degradation of mitochondria was only detectable in oxidative conditions, biogenesis defects were already apparent in untreated patient neurons. This may suggest that mitophagy disruption occurs in response to acute stress. By contrast, the biogenesis pathway may be continually impaired in Parkin-associated Parkinson’s disease. Next, using a mutagenic stress model in combination with Parkin knockdown, we detected an increase in ccf-mtDNA and the cytosolic DNA sensor cGAS. To explore if ccf-mtDNA can act as damage-associated molecular pattern in the brain, we used postmortem tissue from a Parkin mutation carrier and performed single-cell RNA sequencing. In the midbrain lacking Parkin, we found a higher percentage of microglia along with an upregulation of proinflammatory cytokines in these cells. Together, our findings suggest a role for Parkin in the control of mitochondrial biogenesis and mtDNA maintenance, which protects midbrain neurons from neuroinflammation-induced degeneration. Future research in iPSC-derived neuron-microglia co-culture systems could aim at developing PD treatment approaches that target the neuronal release or microglial uptake of ccf-mtDNA.

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

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