Nijmegen Center for Mitochondrial Disorders at the Department of Pediatrics, Radboud University Nijmegen Medical Centre, HB 6500 Nijmegen, The Netherlands.
Hum Mol Genet. 2012 Jan 1;21(1):115-20. doi: 10.1093/hmg/ddr446. Epub 2011 Sep 28.
Mitochondrial complex I (CI) is a multi-subunit enzyme that forms the major entry point of nicotinamide adenine dinucleotide (NADH) electrons into the respiratory chain. Mutations in the NDUFS4 gene, encoding an accessory subunit of this complex, cause a Leigh-like phenotype in humans. To study the nature and penetrance of the CI defect in different tissues, we investigated the role of NDUFS4 in mice with fatal mitochondrial encephalomyopathy, caused by a systemic inactivation of the Ndufs4 gene. We report that the absence of NDUFS4 in different mouse tissues results in decreased activity and stability of CI. This CI instability leads to an increased disconnection of electron influx of the NADH dehydrogenase module from the holo-complex. However, the formation of respiratory supercomplexes still allows formation of active CI in these Ndufs4 knock-out mice. These results reveal the importance of these supramolecular interactions not only for stabilization but also for the assembly of CI, which becomes especially relevant in pathological conditions.
线粒体复合物 I（CI）是一种多亚基酶，它构成了烟酰胺腺嘌呤二核苷酸（NADH）电子进入呼吸链的主要入口。编码该复合物辅助亚基的 NDUFS4 基因突变会导致人类 Leigh 样表型。为了研究不同组织中 CI 缺陷的性质和外显率，我们研究了由 Ndufs4 基因系统失活引起的致命线粒体脑肌病小鼠中 NDUFS4 的作用。我们报告说，不同小鼠组织中 NDUFS4 的缺失导致 CI 活性和稳定性降低。这种 CI 不稳定性导致 NADH 脱氢酶模块的电子流入与全酶的连接断开增加。然而，呼吸超复合物的形成仍然允许这些 Ndufs4 敲除小鼠中形成活性 CI。这些结果表明这些超分子相互作用不仅对稳定而且对 CI 的组装都很重要，这在病理条件下变得尤为重要。
