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.

编码泛素 E3 连接酶 PARKIN 的PRKN基因中的功能缺失变异会导致常染色体隐性遗传早发性帕金森病 (PD)。广泛的体外和体内研究表明，PARKIN 参与线粒体质量控制的多种途径，包括线粒体降解和生物发生。然而，由于实验数据相互矛盾，这些发现存在很大争议。此外，现有的 PARKIN 缺陷小鼠模型未能忠实地再现 PD 表型。因此，我们通过使用一系列条件性 Parkin 基因敲除小鼠，研究了 PARKIN 在衰老过程中和应激反应中线粒体的作用。我们报告说，PARKIN 缺失不会影响老年小鼠大脑、心脏和骨骼肌中的氧化磷酸化 (OXPHOS) 能力和线粒体 DNA (mtDNA) 水平。我们还证明，PARKIN 缺陷不会加剧在携带高水平 mtDNA 突变的小鼠中观察到的大脑缺陷和促炎表型。为了排除Parkin缺陷小鼠胚胎发育过程中激活的补偿机制，我们构建了一个小鼠模型，在成年多巴胺能 (DA) 神经元中诱导 PARKIN 缺失。令人惊讶的是，这些小鼠也没有表现出运动障碍或神经变性，并且在分离的中脑 DA 神经元中没有发现重大转录变化。最后，我们报告了一名患有复合杂合PRKN致病性变异且缺乏 PARKIN 并已发展为 PD 的患者。 PARKIN 缺陷不会损害 OXPHOS 活性或诱导患者骨骼肌中的线粒体病理学。总而言之，我们的结果表明，PARKIN 对于成年哺乳动物组织中的 OXPHOS 功能来说是可有可无的。