Cyclophilin D Promotes Brain Mitochondrial F1FO ATP Synthase Dysfunction in Aging Mice.
Cyclophilin D Promotes Brain Mitochondrial F1FO ATP Synthase Dysfunction in Aging Mice.
复制标题
亲环蛋白 D 促进衰老小鼠脑线粒体 F1FO ATP 合酶功能障碍。
DOI：
10.3233/jad-160822
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Du H
中科院分区：
文献类型：
--
作者：
Gauba E;Guo L;Du H
脑老化是已知的阿尔茨海默病（AD）最强的危险因素。近年来，线粒体缺陷被认为是脑老化与AD的共同机制。因此，阐明老年脑线粒体功能障碍的致病机制对于我们理解AD的发病机制，特别是其散发形式至关重要。亲环素D（Cyclophilin D，CypD）是一种线粒体特异性蛋白。最近的研究表明，F1FO ATP合成酶寡霉素敏感性赋予蛋白（OSCP）是CypD的结合伴侣。CypD与OSCP的相互作用调节F1FO ATP合酶功能并介导线粒体通透性转换孔（mPTP）开放。在这里，我们发现CypD表达增加，CypD/OSCP相互作用增强，OSCP选择性丢失是衰老小鼠脑线粒体的显著变化。沿着这些变化，衰老小鼠的脑线粒体表现出F1 FO ATP合酶活性降低和F1 FO复合物偶联缺陷。相比之下，CypD缺陷小鼠在衰老过程中表现出显著减轻的脑线粒体F1FO ATP合酶功能障碍，线粒体功能相对保留。有趣的是，衰老相关的OSCP丢失也被CypD耗尽显著减弱。因此，对这项研究的最简单解释是CypD促进F1FO ATP合酶功能障碍以及由此导致的衰老大脑中线粒体缺陷。此外，鉴于在AD脑中观察到的CypD和F1FO ATP合酶改变，结果进一步表明CypD介导的F1FO ATP合酶失调是脑老化和AD中线粒体缺陷的共同机制。
Brain aging is the known strongest risk factor for Alzheimer’s disease (AD). In recent years, mitochondrial deficits have been proposed to be a common mechanism linking brain aging to AD. Therefore, to elucidate the causative mechanisms of mitochondrial dysfunction in aging brains is of paramount importance for our understanding of the pathogenesis of AD, in particular its sporadic form. Cyclophilin D (CypD) is a specific mitochondrial protein. Recent studies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binding partner of CypD. The interaction of CypD with OSCP modulates F1FO ATP synthase function and mediates mitochondrial permeability transition pore (mPTP) opening. Here, we have found that increased CypD expression, enhanced CypD/OSCP interaction, and selective loss of OSCP are prominent brain mitochondrial changes in aging mice. Along with these changes, brain mitochondria from the aging mice demonstrated decreased F1FO ATP synthase activity and defective F1FO complex coupling. In contrast, CypD deficient mice exhibited substantially mitigated brain mitochondrial F1FO ATP synthase dysfunction with relatively preserved mitochondrial function during aging. Interestingly, the aging-related OSCP loss was also dramatically attenuated by CypD depletion. Therefore, the simplest interpretation of this study is that CypD promotes F1FO ATP synthase dysfunction and the resultant mitochondrial deficits in aging brains. In addition, in view of CypD and F1FO ATP synthase alterations seen in AD brains, the results further suggest that CypD-mediated F1FO ATP synthase deregulation is a shared mechanism linking mitochondrial deficits in brain aging and AD.