The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

Abstract

The activity of the mitochondrial Permeability Transition Pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. 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, retards, 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.

Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome

“…Several studies have proven a tight bond between increased ROS, PCOS development [ 51 ] and other associated conditions like hyperandrogenism [ 52 ] and MetS [ 53 ]. Elevated ROS are damaging DNA-repair proteins that cause further mutations, OXPHOS malfunction and the production of more ROS, making the vicious cycle complete [ 54 ].…”

Age-Related Changes in Bone-Marrow Mesenchymal Stem Cells

“…When considering the problems of aging of the biological system, the examples of accelerated aging caused by genetic and epigenetic factors are often presented with mitochondria playing a key role [ 27 , 28 , 29 , 30 ]. However, it seems appropriate to talk about programmed delayed aging, the subject of which is as relevant as the problem of accelerated aging.…”

Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer’s Disease

“…Ca 2+ deregulation in neurons develops with age [ 106 ] probably through alterations of L type voltage-gated calcium channels [ 107 ], Ca 2+ buffering capacity of endoplasmic reticulum (ER) [ 108 ] and glutamate-induced Ca 2+ influx [ 109 ]. Such age-related impairment of Ca 2+ homeostasis increases the propensity of mPTP opening [ 110 , 111 ], which further exacerbates intraneuronal Ca 2+ crisis, culminating in a feeding-forward vicious cycle of Ca 2+ -induced mPTP activation during aging. Moreover, increased ROS generation and reduced GSH/GSSG are prominent with age [ 41 , 112 ].…”