The Mitochondrial Transition Pore in Aging
A few papers in recent years have reviewed what is known of the role of the mitochondrial permeability transition pore in aging. Mitochondria are the power plants of the cell, and mitochondrial function is vital to cell and tissue function. Unfortunately, mitochondria become dysfunctional with age, for a variety of reasons that have yet to be firmly traced back to specific root causes. Researchers are engaged in the exploration of proximate causes, such as changing mitochondrial dynamics and loss of mitophagy, the quality control mechanism responsible for removing worn and damaged mitochondria. Changes in the activity of mitochondrial permeability transition pores are also on the list, though as for many of these mechanisms, it is yet to be determined where it fits exactly in the hierarchy of proximate cause and proximate consequence in the final stages of the path to mitochondrial failure in aging.
The mitochondrial permeability transition pore (mPTP) is a mitochondrial inner membrane multicomponent mega-channel that is activated by calcium, oxidative stress, and membrane depolarization. The channel exhibits several conductance states with variable duration. When activated, protons flow into the matrix, while calcium, superoxide, hydrogen peroxide, and other ions flow out of the matrix, thus inhibiting oxidative phosphorylation.
It is now recognized that mitochondrial dysfunction is a major contributor to aging and aging-driven degenerative disease, such as diabetes, heart diseases, cancer, Alzheimer's disease, and Parkinson's disease. Mitochondrial dysfunction in aging is often manifested as the excess production of mitochondrial reactive oxygen species (mROS), calcium overloading, and membrane depolarization. Since these dysfunctions are known to activate mPTP, it can be expected that mPTP activity will be enhanced in dysfunctional mitochondria in aging. Indeed, direct evidence for enhanced mPTP activation in aging and neurodegenerative disease is extensive.
mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca2+, and NAD+. The various pathways that control the channel activity, directly or indirectly, can therefore either inhibit or accelerate aging or retard or enhance the progression of aging-driven degenerative diseases and determine lifespan and healthspan. Autophagy, a catabolic process that removes and digests damaged proteins and organelles, protects the cell against aging and disease. However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP. Autophagy is inhibited in aging cells. Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells, and this inhibition leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases.
The increased activity of mPTP in aging turns autophagy/mitophagy into a destructive process leading to cell aging and death. Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP. Therefore, elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease.