Mitochondrial diseases are considered rare genetic disorders characterized by defects in oxidative phosphorylation (OXPHOS). They can be provoked by mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). MERRF (Myoclonic Epilepsy with Ragged-Red Fibers) syndrome is one of the most frequent mitochondrial diseases, principally caused by the m.8344A>G mutation in mtDNA, which affects the translation of all mtDNA-encoded proteins and therefore impairs mitochondrial function. In the present work, we evaluated autophagy and mitophagy flux in transmitochondrial cybrids and fibroblasts derived from a MERRF patient, reporting that Parkin-mediated mitophagy is increased in MERRF cell cultures. Our results suggest that supplementation with coenzyme Q10 (CoQ), a component of the electron transport chain (ETC) and lipid antioxidant, prevents Parkin translocation to the mitochondria. In addition, CoQ acts as an enhancer of autophagy and mitophagy flux, which partially improves cell pathophysiology. The significance of Parkin-mediated mitophagy in cell survival was evaluated by silencing the expression of Parkin in MERRF cybrids. Our results show that mitophagy acts as a cell survival mechanism in mutant cells. To confirm these results in one of the main affected cell types in MERRF syndrome, mutant induced neurons (iNs) were generated by direct reprogramming of patients-derived skin fibroblasts. The treatment of MERRF iNs with Guttaquinon CoQ10 (GuttaQ), a water-soluble derivative of CoQ, revealed a significant improvement in cell bioenergetics. These results indicate that iNs, along with fibroblasts and cybrids, can be utilized as reliable cellular models to shed light on disease pathomechanisms as well as for drug screening.

中文翻译：

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在MERRF综合征的细胞模型中，Parkin介导的自噬和自噬通量破坏。

线粒体疾病被认为是罕见的遗传性疾病，其特征是氧化磷酸化（OXPHOS）缺陷。它们可能被核DNA（nDNA）或线粒体DNA（mtDNA）的突变引起。MERRF（带红色纤维的肌阵挛性癫痫）综合征是最常见的线粒体疾病之一，主要是由mtDNA中的m.8344A> G突变引起的，它会影响所有mtDNA编码蛋白的翻译，从而损害线粒体功能。在目前的工作中，我们评估了来自MERRF患者的线粒体杂种和成纤维细胞中的自噬和线粒体通量，并报道了MERRF细胞培养物中帕金介导的线粒体增多。我们的研究结果表明，辅酶Q10（CoQ）是电子传输链（ETC）的组成部分，还含有脂质抗氧化剂，防止帕金易位到线粒体。此外，辅酶Q可以作为自噬和线粒体通量的增强剂，从而部分改善细胞病理生理。通过沉默MERRF cybrids中Parkin的表达来评估Parkin介导的线粒体在细胞存活中的重要性。我们的结果表明，线粒体充当突变细胞中的细胞存活机制。为了在MERRF综合征的一种主要受影响细胞类型中证实这些结果，通过直接重编程患者来源的皮肤成纤维细胞来产生突变诱导的神经元（iNs）。辅酶Q的水溶性衍生物Guttaquinon CoQ10（GuttaQ）对MERRF iNs的处理显示出细胞生物能学的显着改善。这些结果表明，iN以及成纤维细胞和杂种，