Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models.
Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models.
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DOI：
10.1016/j.cmet.2015.04.016
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发表时间：
2015-06-02
期刊：
影响因子：
29
通讯作者：
Zeviani M
中科院分区：
文献类型：
--
作者：
Civiletto G;Varanita T;Cerutti R;Gorletta T;Barbaro S;Marchet S;Lamperti C;Viscomi C;Scorrano L;Zeviani M
增加的线粒体成形蛋白Opa 1水平可以提高呼吸链效率并保护组织免受损伤，这表明它可能是对抗线粒体功能障碍的一个有吸引力的目标。在这里，我们表明，Opa 1过表达改善了两个小鼠模型的缺陷线粒体生物能量。结构复合物I组分Ndufs 4（Ndufs 4 −/−）的组成性敲除和复合物IV组装因子Cox 15（Cox 15 sm/sm）的肌肉特异性条件性敲除与Opa 1转基因（Opa 1 tg）小鼠杂交的后代与未处理的非Opa 1过表达模型相比，表现出运动技能和呼吸链活动的改善。虽然Ndufs 4 −/−：：Opa 1 tg小鼠的改善程度适中，但Cox 15 sm/sm：：Opa 1 tg小鼠的嵴超微结构和线粒体呼吸的纠正、运动性能的改善和寿命的延长是显著的。从机制上讲，呼吸链超复合物在Cox 15 sm/sm：：Opa 1 tg小鼠中增加，残留的单体复合物IV稳定。总之，通过控制Opa 1过表达改善嵴形状改善了线粒体疾病的两种小鼠模型。Opa 1过表达改善Ndufs 4 −/−和Cox 15 sm/sm小鼠的表型在双突变体中O2消耗率和呼吸链活性增加线粒体超微结构通过在Cox 15 sm/sm中Opa 1过表达得到纠正呼吸复合物和超复合物在Cox 15 sm/sm：：Opa 1 tg中稳定虽然线粒体疾病有不同的原因，但它们都以氧化磷酸化缺陷为特征。Civiletto等人显示了提高呼吸链效率线粒体成形蛋白OPA 1的过表达改善了两种临床前线粒体生物能量学缺陷模型的表型。
Increased levels of the mitochondria-shaping protein Opa1 improve respiratory chain efficiency and protect from tissue damage, suggesting that it could be an attractive target to counteract mitochondrial dysfunction. Here we show that Opa1 overexpression ameliorates two mouse models of defective mitochondrial bioenergetics. The offspring from crosses of a constitutive knockout for the structural complex I component Ndufs4 (Ndufs4−/−), and of a muscle-specific conditional knockout for the complex IV assembly factor Cox15 (Cox15sm/sm), with Opa1 transgenic (Opa1tg) mice showed improved motor skills and respiratory chain activities compared to the naive, non-Opa1-overexpressing, models. While the amelioration was modest in Ndufs4−/−::Opa1tg mice, correction of cristae ultrastructure and mitochondrial respiration, improvement of motor performance and prolongation of lifespan were remarkable in Cox15sm/sm::Opa1tg mice. Mechanistically, respiratory chain supercomplexes were increased in Cox15sm/sm::Opa1tg mice, and residual monomeric complex IV was stabilized. In conclusion, cristae shape amelioration by controlled Opa1 overexpression improves two mouse models of mitochondrial disease. Opa1 overexpression improves the phenotype of Ndufs4−/− and Cox15sm/sm mice O2 consumption rate and respiratory chain activities are increased in double mutants Mitochondrial ultrastructure is corrected by Opa1 overexpression in Cox15sm/sm Respiratory complexes and supercomplexes are stabilized in Cox15sm/sm::Opa1tg Although mitochondrial diseases have diverse causes, they are all characterized by defective oxidative phosphorylation. Civiletto et al. show that overexpression of the mitochondria-shaping protein OPA1, which improves respiratory chain efficiency, improves the phenotypes of two pre-clinical models of defective mitochondrial bioenergetics.
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