The Mitochondrial Permeability Transition Pore and Loss of Mitochondrial Membrane Potential in Aging
This open access review paper discusses what is known of the role of the mitochondrial permeability transition pore in the age-related decrease of mitochondrial membrane potential. This measure is a lens through which one can view the growing dysfunction of mitochondria with advancing age. Every cell contains hundreds of mitochondria, producing chemical energy store molecules, ATP, to power cellular processes. Reduced rates of ATP production lead to cell and tissue dysfunction. This is thought to be an important contribution to degenerative aging, though exactly how it arises from causative mechanisms, such as mitochondrial DNA damage and whatever leads to reduced expression of nuclear proteins necessary to mitochondrial function, remains to be fully determined.
It is widely reported that the mitochondrial membrane potential, ∆Ψm, is reduced in aging animals. It was recently suggested that the lower ∆Ψm in aged animals modulates mitochondrial bioenergetics and that this effect is a major cause of aging since artificially increased ∆Ψm in C. elegans increased lifespan. Here, I critically review studies that reported reduction in ∆Ψm in aged animals, including worms, and conclude that many of these observations are best interpreted as evidence that the fraction of depolarized mitochondria is increased in aged cells because of the enhanced activation of the mitochondrial permeability transition pore, mPTP.
Activation of the voltage-gated mPTP depolarizes the mitochondria, inhibits oxidative phosphorylation, releases large amounts of calcium and reactive oxygen species (ROS), and depletes cellular NAD+, thus accelerating degenerative diseases and aging. Since the inhibition of mPTP was shown to restore ∆Ψm and to retard aging, the reported lifespan extension by artificially generated ∆Ψm in C. elegans is best explained by inhibition of the voltage-gated mPTP. Similarly, the reported activation of the mitochondrial unfolded protein response by reduction in ∆Ψm and the reported preservation of ∆Ψm in dietary restriction treatment in C. elegans are best explained as resulting from activation or inhibition of the voltage-gated mPTP, respectively.