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

Figure 2

All of the following contribute to ROS production: physiological aging, injury, ischemia, PD, and AD. Injury, ischemia, PD, and AD do so by means of inducing inflammation. Extracellular acidification is a pathological effect of inflammation. A decrease in extracellular pH leads to increased ROS production within the cell which in turn instigates DDR. Aging results in oxidative damage to either mtDNA or electron transport complexes. This instigates defective mROS production. Upon ROS-induced ROS release, ROS can damage nuclear DNA, again inducing DDR. DDR results in proapoptotic pathways that induce mPTP opening and further mROS release. A positive feedback mechanism is initiated in which mPTP openings allow for mROS release which instigates DDR. Simultaneous to the proapoptotic mechanism is the NAD⁺-dependent protective pathways. SIRT3 in particular acts as an inhibitor to mROS release. It is important to note that these mechanisms are opposing and upon depletion of NAD⁺, the proapoptotic pathways dictate mROS release as the protective pathways are unable to perform their function.