The Mitochondrial Transition Pore in Age-Related Mitochondrial Dysfunction

Every cell contains a herd of bacteria-like mitochondria. These are the power plants of the cells, responsible for packaging chemical energy store molecules. They replicate by division, but also fuse together and exchange component parts. For reasons that are far from fully understood, the mitochondria in old tissues are much changed and degraded in comparison to their counterparts in youthful tissue. Their shapes are different, the balance of fusion and fission altered, they generate too little in the way of energy store molecules and too much in the way of oxidative molecules. Some of this is a matter of damage to mitochondrial DNA, which produces its own additional serious set of downstream issues, but much of it seems more akin to a reaction to damage and altered signaling in cells and the surrounding tissue, rather than any inherent malfunction in the mitochondria themselves.

To the degree that this global mitochondrial malaise is a consequence of the accumulated damage and resultant changing character of signaling in aging, then it should end if the root causes of aging are addressed. When the chronic inflammation, altered cell signaling, and issues elsewhere in cell structures are reversed, then we should expect mitochondrial function to improve in turn. This strategy of identifying and fixing root causes is still a minority approach in research and development, however. Most work on mitochondrial aging is focused instead on finding ways to override some of the signals that produce mitochondrial loss of function, to eke out greater capacity for a longer period of time. The history of such approaches doesn't provide much confidence in the ability of the research community to produce large gains via such an approach, however. The best plausible near future therapies are forms of exercise mimetic, perhaps, and those people who exercise a great deal don't live more than a small number of years longer than the rest of us.

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

Mitochondria are central organelles in the cell. They are present in all cells of humans and animals (except red blood cells). They generate cellular energy, produce reactive oxygen species (ROS) that regulate physiological processes, and are involved in the control of cell death. Therefore, it is not surprising that mitochondria could be involved in the normal mammalian aging process. One of the unique characteristics of mitochondria is that they possess their own genetic material in the form of a close circular DNA molecule. According to this latter theory, aging of cells would be due to the constant delivery of ROS inside mitochondria throughout life, damaging mitochondrial DNA which is vulnerable as it is not protected by protein histones or repairing enzymes such as nuclear DNA. The damaged mitochondrial DNA leads to deficiency of key electron transport enzymes and subsequent ROS generation, thus causing a vicious cycle of ROS resulting in a decrease in energy production.

Although a large amount of data support the role of mitochondrial ROS production in aging, other features of mitochondrial physiology and dysfunction, including the mitochondrial permeability transition, have been more recently implicated in the mechanisms of aging. The mitochondrial permeability transition corresponds to the sudden increase in the permeability of the inner mitochondrial membrane to molecules of molecular mass up to 1,500 Da. The opening is due to a nonspecific pore called the mitochondrial permeability transition pore (mPTP) occurring when mitochondria become overloaded with calcium. The sensitivity of the mPTP to calcium is enhanced under oxidative stress conditions, adenine nucleotide depletion, high phosphate concentrations, or membrane depolarization. mPTP opening induces swelling of the organelle matrix, collapse of membrane potential, and uncoupling of oxidative phosphorylation. This phenomenon plays a critical role in different types of cell death. Although the conditions leading to permeability transition are well known, the exact composition of the pore remains unknown.

Currently, a common agreement considers that cyclophilin D (CypD), a soluble protein located within the mitochondrial matrix, is the main partner of the mPTP and that mPTP formation is greatly sensitized by CypD which lowers the calcium threshold required to trigger mPTP opening. The crucial role of CypD has been shown by deletion of the gene in mice, allowing mitochondria to sustain high calcium concentrations and thus conferring major desensitization of mPTP. Two opening states of the pore have been distinguished, a permanent or long-lasting state which is associated with cell death, and a transient opening state having a physiological role by providing a pathway to release ROS and calcium from mitochondria which is also regulated by CypD. The mPTP is now considered to be central in numerous conditions such as heart, brain, or liver ischemia-reperfusion, drug-induced liver injury, age-related neurodegenerative diseases, and accumulating data imply the mPTP in organ dysfunction occurring during aging. Conversely, caloric restriction, which is a proven strategy to delay aging and age-related disease, is associated with the inhibition of mPTP opening.

Recently, a large number of studies demonstrated that the mPTP, which is not definitely characterized at the molecular level, is more sensitive to opening in aged animals and in aging-associated diseases and that its inhibition can enhance lifespan. This appears logical as the cellular modifications occurring during aging, that is, impaired calcium homeostasis, increased oxidative stress, oxidative modifications of proteins, enhancement of CypD level, and apoptosis, are factors contributing to and modulated by mPTP opening. However, doubts persist about the involvement of mPTP in the progression of aging and definitive experimental proofs of mPTP involvement have to be provided to demonstrate whether it is a cause or a consequence of aging. A better knowledge of the structural composition and of the regulation of the pore will probably help to elucidate the role of mPTP in longevity and healthspan.

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