There is an increased interest in the mitochondrial permeability transition pore as a target for interventions that might improve mitochondrial function in aging. Mitochondria are the power plants of the cell, bacteria-like factories that package the chemical energy store molecule ATP via an energetic process of reactions. Mitochondria become dysfunction in aged tissues for reasons that include changes in their ability to divide and fuse together, and a faltering in the quality control mechanism of mitophagy. This loss of function is particularly important in the aging of energy-hungry tissues such as the muscles and brain.
The research community is at present largely focused on trying to reverse specific symptoms of mitochondrial dysfunction, such as lower NAD+ levels, or changes in gene expression related to mitochondrial dynamics, or changes in mitochondrial permeability transition pore behavior. It isn't clear as to how effective these options will turn out to be, whether they are targeted close enough to the root of the problem to make a meaningful difference. There are also efforts to replace mitochondria, or eliminate those that are dysfunctional, and copy mitochondrial genes to the cell nucleus as a backup source of necessary proteins for mitochondrial function. These will probably be better approaches, but these are still comparatively early days in which there is all too little data for efficacy.
A better understanding of the cellular and molecular mechanisms underlying aging is central to the successful development and clinical translation of novel therapies and prevention strategies. Recent work has demonstrated that changes in mitochondrial permeability transition pore (mPTP) function may contribute directly to cellular dysfunction with aging. These changes include increases in reactive oxygen species (ROS) production, induction of cellular senescence (particularly in aging stem cells), and activation of the inflammasome, the latter contributing directly to the chronic state of inflammation often referred to as "inflammaging". mPTP dysfunction has been cited as a key factor in neurodegenerative pathologies through its role in collapsing mitochondrial membrane potential, repressing mitochondrial respiratory function, releasing mitochondrial Ca2+ and cytochrome c, and enhancing ROS generation. Thus, the mPTP has received increased attention as a potential therapeutic target.
The relationship between the mPTP and the generation of mitochondrial reactive oxygen species (mROS) has attracted significant interest within the context of aging and age-related tissue degeneration. Recently, it was found that mROS can stimulate the opening of the mPTP, which can lead to further mROS production and release. This positive feedback mechanism ultimately leads to an excessive amount of ROS accumulation. ROS accumulation in turn damages nuclear DNA, activates pro-apoptotic signaling pathways, and drives cellular aging. On the other hand, ROS can in some cases activate protective pathways, decrease stress on the mitochondria, and increase lifespan. It is currently thought that the mPTP plays an important role in integrating the effects of mROS and hence may play a vital role in the aging process. In this review, we discuss the various mechanisms inducing activation of the mPTP and the age-associated cell damage seen as a byproduct of mPTP activation. Furthermore, we discuss potential therapies that target the mPTP and may therefore inhibit the effects of aging and injury.