Edgar Daniel, Shabalina Irina, Camara Yolanda, Wredenberg Anna, Calvaruso Maria Antonietta, Nijtmans Leo, Nedergaard Jan, Cannon Barbara, Larsson Nils-Göran, Trifunovic Aleksandra
Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Cell Metab. 2009 Aug;10(2):131-8. doi: 10.1016/j.cmet.2009.06.010.
The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature aging phenotype. We have now performed molecular analyses to determine the mechanism whereby these mtDNA mutations impair respiratory chain function. We report that mitochondrial protein synthesis is unimpaired in mtDNA mutator mice consistent with the observed minor alterations of steady-state levels of mitochondrial transcripts. These findings refute recent claims that circular mtDNA molecules with large deletions are driving the premature aging phenotype. We further show that the stability of several respiratory chain complexes is severely impaired despite normal synthesis of the corresponding mtDNA-encoded subunits. Our findings reveal a mechanism for induction of aging phenotypes by demonstrating a causative role for amino acid substitutions in mtDNA-encoded respiratory chain subunits, which, in turn, leads to decreased stability of the respiratory chain complexes and respiratory chain deficiency.
线粒体DNA突变小鼠存在高水平的线粒体DNA点突变和线性缺失，导致进行性呼吸链功能障碍和早衰表型。我们现在进行了分子分析，以确定这些线粒体DNA突变损害呼吸链功能的机制。我们报告称，线粒体蛋白合成在mtDNA突变小鼠中未受损害，这与观察到的线粒体转录本稳态水平的微小变化一致。这些发现驳斥了最近关于带有大缺失的环状线粒体DNA分子导致早衰表型的说法。我们进一步表明，尽管相应的线粒体DNA编码亚基合成正常，但几种呼吸链复合物的稳定性仍严重受损。我们的发现揭示了一种衰老表型诱导机制，证明了线粒体DNA编码的呼吸链亚基中的氨基酸替代具有因果作用，进而导致呼吸链复合物稳定性降低和呼吸链缺陷。
