Researchers here outline a model of mitochondrial dysfunction as a contributing cause of aging that centers around mitochondrial permeability transition pores, molecular structures that govern the permeability of the inner mitochondrial membrane. These pores are known to be associated with the mitochondrial stress and functional failure that is observed in the biochemistry of numerous age-related diseases, but the degree to which this is a consequence versus a cause of damage is one of many open questions in the cellular biology of aging. The more usual focus of the mitochondrial contribution to aging is damage to mitochondrial DNA, and consequent operational failure due to loss of specific proteins needed for normal mitochondrial function. This is the basis for the SENS rejuvenation research approach of copying mitochondrial genes into the cell nucleus to provide a backup source of these proteins.
Oxidative stress in animals is strongly correlated with aging and lifespan, as predicted by the free radical theory of aging (FRTA). Because most reactive oxygen species (ROS) are generated in the mitochondria (mROS), in close proximity to mitochondrial DNA (mtDNA) and the mitochondrial oxidative phosphorylation system, it was suggested that oxidative damage to mtDNA, mitochondrial proteins, and phospholipids is the direct cause of aging and determines lifespan. This more specific version of FRTA was named the mitochondrial free radical theory of aging. The evidence supporting mFRTA is extensive.
The mitochondrial permeability transition pore (mPTP) is an inner membrane protein complex that can be induced to form a nonselective channel. The channel exhibits several conducting states that can open for short (milliseconds) or long (seconds) periods, and with different permeabilities. Full opening of the mPTP results in increased production of mROS and release of most associated metabolites. As a result, the mitochondrial membrane potential collapses, oxidative phosphorylation and mitochondrial metabolism are inhibited, the matrix swells, and on prolonged opening the outer membrane ruptures, releasing intermembrane space proteins. Moreover, the release to the cytosol of ROS and metabolites disrupts cellular homeostasis and increases oxidative damage. Prolonged pore opening in a large number of mitochondria in the cell can lead to cell death by necrosis or similar pathways.
Frequent and extended opening of the mPTP, with its associated bursts of mROS, can overwhelm the cell's antioxidant systems resulting in extensive DNA damage. A more moderate ROS production by mitochondria may not lead to strong pro-apoptotic signals but is sufficient to trigger various mechanisms that adjust cellular processes and protect the mitochondria and the cell from damage. This level of ROS formation is mostly contained by antioxidant systems. When their capacity is exceeded, the increased oxidative stress activates the mPTP. While short, infrequent opening of the mPTP also triggers protective pathways, increasing the frequency and duration of the mPTP is associated with more persistent oxidative damage that may result in aging and even cell death.
Because it is difficult to untangle the protective effects of mROS from its deleterious effects, the concept of FRTA has not been widely accepted. Instead, a consensus is emerging in which the balance between mROS-induced protective pathways and cell damage-induced apoptotic pathways is somehow integrated in the mitochondria to determine the progression of aging and ultimately cell death. Here, we propose that these contrasting signals are integrated at the level of the mPTP, which largely determines the rate of aging and ultimately lifespan by the frequency and duration of pore openings.
The hypothesis that mPTP is the driver of aging can be considered a refinement of mFRTA as it is proposed that much of the oxidative damage to the mitochondria itself results from the activation of mPTP and that most of the effects of 'mitochondrial dysfunction' and mROS on aging and lifespan are mediated through activation of the mPTP. By controlling both the depletion of cellular NAD+ and the induction of a strong DNA damage response, mPTP can drive aging and death of postmitotic cells as well as senescence in mitotic cells. Moreover, it is likely that mPTP opening also mediates mROS-driven inflammation, because the formation of the NPLR3 inflammasome appears to depend on opening of the mPTP, and chronic activation of the mPTP (by deletion of MICU1) was found to extend the pro-inflammatory response in response to injury.
The fact lifespan can be extended experimentally in several animal models of aging, and the findings that in many cases lifespan extension appears to depend on mROS signaling are often cited as the strongest evidence against mFRTA. Evidently, in these cases, mROS initiate the mitochondria protection pathways at an early age and this leads to lifespan extension. The mitochondrial protection pathways invariably lead to inhibition of the mPTP, whether indirectly by inhibition of mROS production, increased antioxidant protection, increased mitophagy, and increased mitochondrial biogenesis, or by direct inhibition of mPTP activation. In a study of a very large number of C. elegans lifespan modulations by mutations and environmental manipulations, it was shown that lifespan correlates negatively with the frequency of 'mitoflashes' at an early adult age. If one accepts the interpretation that 'mitoflashes' signal the opening of the mPTP, it could be argued that in all these cases lifespan extension is the result of inhibition of mPTP opening in early adulthood. Metformin, the first drug approved for clinical trials for retarding the progress of human aging, was shown to inhibit the mPTP. Thus, it is likely that in most, if not all, manipulations that extend animal lifespan, the mPTP is inhibited, directly or indirectly.
In summary, we suggest that the mPTP itself is the elusive site of integration of the contrasting pro- and antiapoptotic signals that determine the rate of progression to aging. While many processes upstream of the mPTP (e.g., oxidative phosphorylation, electron transport, mROS production, mitochondrial antioxidant defense, mitophagy, mitochondrial biogenesis) are also affected by the various protection mechanisms, it is likely that these upstream processes affect aging largely through their effects on mPTP activation. There is still much to be learned about the composition and structure of the mPTP, the mechanisms that control mPTP opening, the various activation states of the mPTP, the extent and types of ions and metabolites that are released, and how the progression of aging affects these processes. The progression of aging to death does not follow a uniformly shaped curve in all animals. An animal's lifespan can be determined by the failure of one particular critical organ, by either postmitotic or mitotic cells, and differences between the control of the mPTP in different organs, and different types of cells, may account for some of the differences between species. Further studies of the control of mPTP in aging can open the door to a much better understanding of the determinants of longevity.