The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore.
The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore.
复制标题
从线粒体ROS到衰老的途径贯穿线粒体渗透性转换孔。
DOI：
10.1111/acel.12650
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发表时间：
2017-10
期刊：
影响因子：
7.8
通讯作者：
Hoek JB
中科院分区：
文献类型：
--
作者：
Rottenberg H;Hoek JB
线粒体活性氧（mROS）的过度产生与线粒体和细胞氧化损伤、衰老和退行性疾病密切相关。然而，mROS也诱导线粒体保护途径，减缓衰老，抑制细胞死亡，并增加寿命。最近的研究表明，由mROS和线粒体钙超载触发的线粒体通透性转换孔（mPTP）的激活在老年动物和人类以及衰老相关的退行性疾病中增强。mPTP开放引发mROS的进一步产生和释放，其破坏线粒体和核DNA、蛋白质和磷脂，并且还释放在膜间隙中水解的基质NAD，从而有助于细胞NAD的消耗，加速老化。对钙转运蛋白的氧化损伤导致钙超载和mPTP更频繁的开放。由于衰老增强了mPTP的开放，而mPTP的开放加速了衰老，因此我们认为mPTP的开放推动了衰老的进展。mPTP的激活不仅受到mROS诱导的线粒体保护途径的直接和间接调节，还受到DNA损伤诱导的促凋亡信号的直接和间接调节。我们认为，这些对比信号的整合mPTP在很大程度上决定了细胞衰老的速度和细胞死亡的开始，从而动物的寿命。控制mPTP激活对衰老进程至关重要的建议可以解释关于mROS对健康和寿命的有益和有害影响的相互矛盾和令人困惑的证据。
Excessive production of mitochondrial reactive oxygen species (mROS) is strongly associated with mitochondrial and cellular oxidative damage, aging, and degenerative diseases. However, mROS also induces pathways of protection of mitochondria that slow aging, inhibit cell death, and increase lifespan. Recent studies show that the activation of the mitochondrial permeability transition pore (mPTP), which is triggered by mROS and mitochondrial calcium overloading, is enhanced in aged animals and humans and in aging‐related degenerative diseases. mPTP opening initiates further production and release of mROS that damage both mitochondrial and nuclear DNA, proteins, and phospholipids, and also releases matrix NAD that is hydrolyzed in the intermembrane space, thus contributing to the depletion of cellular NAD that accelerates aging. Oxidative damage to calcium transporters leads to calcium overload and more frequent opening of mPTP. Because aging enhances the opening of the mPTP and mPTP opening accelerates aging, we suggest that mPTP opening drives the progression of aging. Activation of the mPTP is regulated, directly and indirectly, not only by the mitochondrial protection pathways that are induced by mROS, but also by pro‐apoptotic signals that are induced by DNA damage. We suggest that the integration of these contrasting signals by the mPTP largely determines the rate of cell aging and the initiation of cell death, and thus animal lifespan. The suggestion that the control of mPTP activation is critical for the progression of aging can explain the conflicting and confusing evidence regarding the beneficial and deleterious effects of mROS on health and lifespan.
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影响因子：
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