The Reduction in the Mitochondrial Membrane Potential in Aging: The Role of the Mitochondrial Permeability Transition Pore

Abstract

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 mROS, 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.

Melamine Exacerbates Neurotoxicity in D-Galactose-Induced Neuronal SH-SY5Y Cells

“…Our data showed that Mel treatment on SH-SY5Y neuronal cells attenuated the antioxidant activity causing oxidative stress conditions. This result was in accordance with the previous reports that showed increased oxidative stress in the hippocampal region of adult rats upon treatment with Mel [ 15 ]. Further in our study, we found that when DG-treated cells were exposed to Mel, more pronounced decrease in the antioxidant activity of the cells occurred, hence depicting huge oxidative stress in the cotreated group ( Figure 4(a) ).…”

“…Aging is a complex biological process associated with a gradual decline in physiological functions, including those of the brain. The accumulation of oxidative stress and dysregulation of apoptosis are key contributors to the aging-related degeneration of neuronal cells [ 14 , 15 ].…”

“…One of the distinguishing characteristics of an early marker of apoptosis is the disturbance of active mitochondria which includes changes in the oxidation-reduction potential and modifications in the membrane potential. Apoptosis is mediated by cysteine proteases called caspases among which Casp3 executes proteolytic cleavage and cell death process [ 14 , 15 ].…”

Direct toxicity of cigarette smoke extract on cardiac function mediated by mitochondrial dysfunction in Sprague-Dawley rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes

“…Increased Ca 2+ and ROS both activate a large conductance channel in the mitochondrial inner membrane, the mitochondrial permeability transition pore (mPTP), whose opening disrupts the mitochondrial membrane potential (ΔΨ m ) [ 24 ]. We thus examined whether CSE treatment induces mPTP opening by assessing the attenuation of calcein fluorescence from mitochondrial regions labeled by TMRE (see methods).…”

“…Abnormal cytosolic Ca 2+ overload induces mitochondrial Ca 2+ influx via mitochondrial Ca 2+ uniporters, both of which can lead to enhanced mitochondrial ROS production [ 29 ]. This can activate a large conductance channel in the mitochondrial inner membrane (IMM) known as mitochondrial permeation transition pore (mPTP), and opening of mPTP decrease ΔΨm [ 24 ], that collapse protonmotive force and inhibits ATP synthesis. Prolonged opening of the mPTP allows cytoplasmic solutes to flow into the mitochondria, causing massive swelling of the IMM, rupture of the outer membrane, that cause cytochrome c release and cell death [ 30 ].…”