Mitochondria and aging: A role for the mitochondrial transition pore?

Mathieu Panel, Bijan Ghaleh, Didier Morin

https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.12793

The mitochondrial permeability transition pore (mPTP) is a protein that is formed in the inner membrane of the mitochondria under certain pathological conditions such as traumatic brain injury and stroke. Induction of the permeability transition pore, referred to as the mitochondrial membrane permeability transition (mPT), can lead to mitochondrial swelling and cell death through apoptosis or necrosis depending on the particular biological setting.

Recently, the mPTP has been implicated in the development of the ageing process.

In this paper, the authors review the potential role of mPTP in normal aging and in age-associated diseases.

CALCIUM HOMEOSTASIS, mPTP AND AGEING                                                                    Elevated matrix calcium was the first factor described to activate mPTP opening, and aging alters cytosolic calcium handling. This has been sown in the heart, where aging impairs the myocardial calcium transport system and calcium storage capacities. This was also confirmed in myocytes isolated from human right atria.   

ROS GENERATION, mPTP AND AGEING                                                                              

It is well known that mitochondria are producers of reactive oxygen species (ROS). Evidence suggests that aging involves a change in ROS regulatory processes encompassing a decline in mitochondrial function and an increase in ROS generation. The possible link between ROS production and mPT during ageing is that ROS decrease the calcium concentration needed for mPTP opening and thus sensitize it. This was observed with cardiolipin, a phospholipid that is specific of mitochondria and is susceptible to lipid peroxidaztion by ROS. Oxidized cardiolipin was shown to sensitize heart mitochondria to mPTP opening, and the level of oxidised cardiolipin increases with aging.

MEMBRANE POTENTIAL, mPTP AND AGEING

Several studies have shown that the mitochondrial membrane potential is lower in aged cells. This may have consequences on mPTP opening, as mPTP is a voltage-dependent channel which tends to open upon depolarization. It has been shown in vitro that depolarization induces mPTP opening when mitochondria have been suitably loaded with calcium.

NAD+, mPTP AND AGEING

Several data suggest that aging reduces cellular nicotinamide adenine dinucleotide (NAD+). This was observed in mice, C. elegans and human tissues. Conversion of NAD+ to NADH plays a key role in mitochondrial metabolism. A drop in NAD+ cellular levels can therefore limit NADH generation.  This decreases mitochondrial membrane potential, which increases the frequency and duration of mPTP opening. In turn, mPTP opening causes the release of NAD+ from mitochondria and its depleiton, therefore inducing a vicious circle.
Another important consequence of mitochondrial NAD+ depletion is the inhibition of mitochondrial sirtuin (SIRT, a class of deacetylases) activity, especially SIRT3. This enzyme plays a critical role in the protection of mitochondria and, more particularly, it was shown to inhibit mPTP opening.

In conclusion, a large number of studies demonstrated that the mPTP is more sensitive to opening in aged animals and in aging-associated diseases. However, doubts persist  and definitive experimental proofs of mPTP involvement have to be provided to demonstrate whether it is a cause or a consequence of aging.