The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore

Abstract

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.

Keywords: NAD; aging; calcium; mitochondria; permeability transition; reactive oxygen species.

Figure 1

mPTP integration of protective and apoptotic signals determines the rate of cell aging. In cells from young animals, the opening of the mPTP is infrequent and most metabolism‐related increase in mROS production induces mROS signaling to the nucleus, largely through AQP8 (green arrow from mitochondria to nucleus), activating the DNA damage response (DDR) that triggers PARP1 and a number of mitochondria protective pathways (green arrow from nucleus to mitochondria), such as the antioxidant defenses (Nrf2), the mitochondrial unfolded protein response (UPRmt), and sirtuins (e.g., Sirt1, Sirt3), all of which inhibit the mPTP directly and indirectly and prevent more frequent opening of mPTP. Nevertheless, with time, oxidative damage resulting from the frequent and prolonged activity of mPTP (red arrows) damages both mitochondrial electron transport complexes and calcium transporters, particularly in the ER, resulting in increased mROS production and mitochondrial calcium overloading that further enhance mPTP opening. Moreover, the increased release of mROS by the mPT also increases oxidative damage to nuclear DNA resulting in increased pro‐apoptotic signaling (red arrows from nucleus to mitochondria) inducing transfer of P53 and p66sch and other pro‐apoptotic proteins to the mitochondria where they enhance mPTP opening. As aging progresses, the increased mPTP opening also depletes mitochondrial NAD ⁺, inhibiting the protective effect of Sirt3 and further stimulating mPTP opening. Finally, the increased oxidative damage to nuclear DNA increases PARP1 activity leading to nuclear NAD ⁺ depletion, which inhibits the nuclear sirtuins (e.g., Sirt1), weakening the mitochondrial protective pathways and further enhancing mPTP activation. This cycle continues, leading to longer and more frequent mPTP activation events, weaker and weaker protection signaling and stronger and stronger pro‐apoptotic signaling, eventually leading to irreversible opening of mPTP, mitochondrial swelling, rupture of the outer membrane, and cell death. The mROS damaging effects that enhance mPTP activation are in red and mROS signaling and the protective pathways are in green (see text for more details).