Department of Pediatrics, Amalia Children's Hospital, RIMLS, RCMM, Radboudumc, Nijmegen, The Netherlands.
Department of Biochemistry (286), RIMLS, RCMM, Radboudumc, Nijmegen, The Netherlands.
Brain. 2022 Mar 29;145(1):45-63. doi: 10.1093/brain/awab426.
Mitochondria are small cellular constituents that generate cellular energy (ATP) by oxidative phosphorylation (OXPHOS). Dysfunction of these organelles is linked to a heterogeneous group of multisystemic disorders, including diabetes, cancer, ageing-related pathologies and rare mitochondrial diseases. With respect to the latter, mutations in subunit-encoding genes and assembly factors of the first OXPHOS complex (complex I) induce isolated complex I deficiency and Leigh syndrome. This syndrome is an early-onset, often fatal, encephalopathy with a variable clinical presentation and poor prognosis due to the lack of effective intervention strategies. Mutations in the nuclear DNA-encoded NDUFS4 gene, encoding the NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) of complex I, induce 'mitochondrial complex I deficiency, nuclear type 1' (MC1DN1) and Leigh syndrome in paediatric patients. A variety of (tissue-specific) Ndufs4 knockout mouse models were developed to study the Leigh syndrome pathomechanism and intervention testing. Here, we review and discuss the role of complex I and NDUFS4 mutations in human mitochondrial disease, and review how the analysis of Ndufs4 knockout mouse models has generated new insights into the MC1ND1/Leigh syndrome pathomechanism and its therapeutic targeting.
线粒体是一种小型的细胞成分，通过氧化磷酸化（OXPHOS）产生细胞能量（ATP）。这些细胞器的功能障碍与一组异质的多系统疾病有关，包括糖尿病、癌症、与年龄相关的病理和罕见的线粒体疾病。就后者而言，编码第一氧化磷酸化复合物（复合物 I）亚基的基因突变和组装因子诱导孤立的复合物 I 缺陷和 Leigh 综合征。这种综合征是一种早发性、常致命的脑病，由于缺乏有效的干预策略，其临床表现和预后各不相同。核 DNA 编码的 NDUFS4 基因突变，编码复合物 I 的 NADH：泛醌氧化还原酶亚基 S4（NDUFS4），在儿科患者中诱导“线粒体复合物 I 缺陷，核型 1”（MC1DN1）和 Leigh 综合征。已经开发了多种（组织特异性）Ndufs4 敲除小鼠模型来研究 Leigh 综合征的发病机制和干预测试。在这里，我们回顾和讨论了复合物 I 和 NDUFS4 突变在人类线粒体疾病中的作用，并回顾了 Ndufs4 敲除小鼠模型的分析如何为 MC1ND1/Leigh 综合征的发病机制及其治疗靶点提供了新的见解。
