New Hope Biomedical R&D, 23 W. Bridge Street, New Hope, PA, 18038, USA.
Department of Anatomy, Pathology and Cell Biology, MitoCare Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
Aging Cell. 2017 Oct;16(5):943-955. doi: 10.1111/acel.12650. Epub 2017 Jul 31.
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.
线粒体活性氧物质（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 也会诱导保护线粒体的途径，这些途径可以减缓衰老、抑制细胞死亡并延长寿命。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与衰老相关的退行性疾病中增强。mPTP 的开放会引发进一步的 mROS 产生和释放，从而损害线粒体和核 DNA、蛋白质和磷脂，并释放基质 NAD，其在膜间空间中水解，从而导致细胞 NAD 的消耗加速衰老。钙转运体的氧化损伤导致钙超载和 mPTP 更频繁地打开。由于衰老增强了 mPTP 的开放，并且 mPTP 的开放加速了衰老，因此我们认为 mPTP 的开放驱动了衰老的进展。mPTP 的激活不仅受到由 mROS 诱导的线粒体保护途径的直接和间接调节，还受到由 DNA 损伤诱导的促凋亡信号的调节。我们认为，这些相反信号通过 mPTP 的整合在很大程度上决定了细胞衰老的速度和细胞死亡的启动，从而决定了动物的寿命。控制 mPTP 激活对于衰老的进展至关重要的观点可以解释关于 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。
