Acín-Pérez Rebeca, Bayona-Bafaluy María Pilar, Fernández-Silva Patricio, Moreno-Loshuertos Raquel, Pérez-Martos Acisclo, Bruno Claudio, Moraes Carlos T, Enríquez José A
Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Miguel Servet, 177, Zaragoza 50013, Spain.
Mol Cell. 2004 Mar 26;13(6):805-15. doi: 10.1016/s1097-2765(04)00124-8.
A puzzling observation in patients with oxidative phosphorylation (OXPHOS) deficiencies is the presence of combined enzyme complex defects associated with a genetic alteration in only one protein-coding gene. In particular, mutations in the mtDNA encoded cytochrome b gene are associated either with combined complex I+III deficiency or with only complex III deficiency. We have reproduced the combined complex I+III defect in mouse and human cultured cell models harboring cytochrome b mutations. In both, complex III assembly is impeded and causes a severe reduction in the amount of complex I, not observed when complex III activity was pharmacologically inhibited. Metabolic labeling in mouse cells revealed that complex I was assembled, although its stability was severely hampered. Conversely, complex III stability was not influenced by the absence of complex I. This structural dependence among complexes I and III was confirmed in a muscle biopsy of a patient harboring a nonsense cytochrome b mutation.
氧化磷酸化（OXPHOS）缺陷患者中一个令人费解的现象是，仅一个蛋白质编码基因发生遗传改变却伴有复合酶复合物缺陷。特别是，线粒体DNA编码的细胞色素b基因突变与复合酶I + III联合缺陷或仅与复合酶III缺陷相关。我们在携带细胞色素b突变的小鼠和人类培养细胞模型中重现了复合酶I + III联合缺陷。在这两种模型中，复合酶III的组装均受到阻碍，并导致复合酶I的量严重减少，而在复合酶III活性受到药物抑制时未观察到这种情况。对小鼠细胞进行代谢标记显示，复合酶I已组装完成，尽管其稳定性受到严重影响。相反，复合酶III的稳定性不受复合酶I缺失的影响。在一名携带细胞色素b无义突变的患者的肌肉活检中证实了复合酶I和III之间的这种结构依赖性。
