Targeting the Mitochondrial Permeability Transition Pore to Prevent Age-Associated Cell Damage and Neurodegeneration

Figure 3

The components of the mPTP are of great controversy. However, despite this, CyPD and the controversial F₁F₀ (F)-ATP synthase are shown as pore constituents. VDAC, while not considered to be part of the mPTP, is thought to be how mROS, Ca²⁺, etc. are shuttled from the intermembrane space to the cytosol. mROS release through the mPTP leads to DNA and Ca²⁺ transporter damage. DNA damage induces DDR or DNA damage response. DDR subsequently induces both proapoptotic signals and protective pathways. Proapoptotic signals recruit p53 and p66Shc which act upon the mPTP (p53 specifically interacts with CypD, and p66Shc targets the intermembrane space generating ROS) to further induce mPTP openings. Oxidative damage to Ca²⁺ transporters can lead to calcium overloading and subsequent increased mPTP openings. MCU in particular can be affected by oxidative damage, leading to a disruption in mitochondrial Ca²⁺ levels. Protective pathways such as PARP1 aid in DNA repair, and SIRT3 inhibit mROS production. As further oxidative damage to DNA takes place, both protective pathways continue to utilize NAD⁺. NAD⁺ depletion can result, leading to an inactivation of protective pathways. In turn, the proapoptotic signals are left unchallenged and mPTP openings become more frequent.