Is the Mitochondrial Permeability Transition Pore at the Center of Mitochondrial Contributions to Aging?
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.
This is a highly credible theory of aging and, as the paper suggests, should be considered a refinement of the more general mitochondrial theory of aging. This theory also establishes the link between Aubrey de Grey's ideas on mitochondria and Nick Lane's idea about the role of mROS in regulating respiration rates.
I consider this to be the most significant development in aging research in the past 10 years.
Well, seems 'aging' open the mPTP and mPTP opening causes 'aging'. Nice review though.
mPTP at the nexus of ATPase dimers seems the best explanation to me. Loss of cristaea leads to de-dimerization or de-dimerization leads to loss of cristaea integrity.
Its all dimers these days. Even the closely associated TOM outer membrane import pore forming TOM40 subunits do the dimer. http://www.cell.com/cell/fulltext/S0092-8674(17)30819-X
More poignantly for Abelard I suppose, the TOM complex associated OM14 appears to coordinate the cytosolic ribosomes for co-translation of nuclear encoded mito proteins. https://www.ncbi.nlm.nih.gov/pubmed/25487825?dopt=Abstract
The question for the allotropists then is how well does this system handle the hydrophobic mito-encoded subunits that the mitoribosomes on the opposite side of the membrane are optimized to translate? Perhaps not so much.
yes john, frustrating that they don't elucidate the root cause of mPTP opening increasing in duration and frequency - is it driven by the mitochondria or the nucleus? It seems it is like a see-saw, damage to one ultimately pulls protection from the other.
I assume you've read this:
https://www.ncbi.nlm.nih.gov/pubmed/18442324
Showing mitochondrial DNA and metabolic rate are the two main drivers determining max lifespan in mammals?
Elucidating the root cause of mPTP opening is the next step in the research. I suspect this is a regulated process and the regulation itself breakdown, thus causing the mPTP openings to stay open longer than their supposed to. Is this regulation controlled by the mDNA, or is it something in the pore itself? Obviously this is the next step in discovery.
This finding is not the complete answer. But its a major step in the right direction AND it definitely narrows the scope down, which is why it is so significant.
Hi ! Interesting,
just my 2 cents, I don't know but I think it is the calcium overload the reason the mPTP opens up and could stay open for much longer (thus emptying the cytochrome). Calcium ions directly control mPTP, and overloading (calcification) creating pore opening when in excess. Inversely, magnesium ions, inhibit calcium ions action on mPTP, they close the mPTP. The reasoning being that magnesium recoils/recompacts the deconsended/decompacted chromosomes and like potassium ions or sodium ions it increases ATP pumps activity in mitochondria ETC. Also, it is because of a disturbance in redox, redox is extremely sensible to these mitochondrial changes and also, outside mitochondria in cytosol and extra-cellularly. My guess it is combination of mitochondrial membrane potential changes (millivoltage), due to a stress signal (most likely an oxidative one, possible mitochondrial DNA damage) and of millivoltage of redox (it only takes about an increase of +30mV for mPTP to open). Disturbing the balance of redox or the ETC's eletron flow creates that (and it is manifested as calcium loading and then, BID/BAD/BAX and other genes come to the mitoinnermembrane/outermembrane bilayer and signal mPTP opening to empty the cytochrome. A mechanism that is directly about curbing cancer by auto-destruction of mitochondria/towards senescence effete 'giant mitcohndria'; a response to inflammation and damage (which contribute to cancer when it goes to a low threshold. In fact, cancer tumor cells have different membrane potential than healthy cells or dying ones, they maintain potential and avoid mPTP opening (chemothearpy accelerates mPTP opening in cancer cells)).
It's true that mtDNA and metabolic rate are Very strong determinants of MLSP in mammals... but even there there are shades of grey. One study had showed that ATP levels in mitochondria are about 4000 units between 20-40 years old, and by 80-90 years old, the mitochondrias output 2000 units. So you lose nearly half of ATP power over some 60-70 years. Another study showed that centenarians/LLI (Long-Lived Individuals) people have a massive mitofusion that happens to 'salvage' of the failing mitochondrias that don't produce enough ATP at over a 100 years old. The mitochondrias in LLIs 'joined together' and 'survived' by joining together (fusion) in a huge mass of 'connected/fused' mitochondrias. And the kicker is : the ATP output was 'saved', meaning this restructuring was enough to compensate for individual mitochondria failing to make enough ATP as they aged - when together/fused they made 'just' enough ATP; and thus, the person could live to over a 100 years old (it is a requirement for over a 100 years old life). Demonstrating the 'strength in numbers'; and that a network of 'bad' mitochondrias linked together, is still better than tons of them all separated. I think the reason is because they don't go to proteasome, they are saved by this fusion; while the seperated ones whom did not join 'the pack'..they're lost and will go to proteasome for mitophagy/destruction; or else, if too big to be phaged, linger and become giant senescent effete that produce ROS and contribute to inflammation/SASP. We can also infer that this linking enable a stopping of mPTP opening (that would be happening in the lingering ones). If they produce more/enough ATP then yes the mPTP is closed for the ETC is dependent on it and on electron flow/cytochrome containement.
One of the most powerful blocker of mPTP opening is Bcl gene (Bcl-X Bcl2), tumor cells high-jack that and combat chemotherapy; when this gene is blocked tumors have much more difficulty stopping mPTP opening. The mPTP is thus controlled many factors (not one single one), and is very unstable; it takes very little to make an opening of it. It truly is 'Porous' and not very impermeable. So, redox, calcium overload, ETC changes, electron loss during ETC, cytochrome c loss, mV change, oxidative stress outside/inside and tons more things.
And mitochondrial DNA and metabolic rate are among the strongest indicators of specie MLSP, Complex I and III in the inner mitochondrial membrane'S ETC produce ROS; and the mitochondrial ROS emission has been correlated to MLSP in mammals in several organs (heart, liver and brain for example). This mtROS emission also governs metabolic rate (higher metabolic rates can create higher mtROS production; it goes in tandemn. but it is not a 1:1 thing, as some outliers such as humans, certain bats, naked mole rats and other long-lived animals - actually have high levels of ROS - but they have much better antioxidative, DNA repair and proteasomic systems - thus ROS emission impact is lessened in these outliers, despite having Higher Metabolism). This means evolution 'found ways' to 'get around' circumvent the 'impossible'. Like for example, in mammals, evolution made pressure on mitochondrial IMM OMM (inner/outer membrane) phopholipid fatty acid composition - being changed for less peroxidizing fatty acids (ex: DHA 22:6 was replaced with 20:4 (arachidonic acid), 18:2 (linoleic acid) was replaced with monounsaturates (18:1, oleic acid). These little changes made the mitochondrias' membranes 'sturdier' and lipid peroxidation 'proof'. For saturated and low-unsaturated fats (monounsaturates) have very little peroxidation power - while Unsaturated fatty acids/Polyunsaturates are highly peroxidative and contribute to major damage in the mitochondrais (this happens daily and is why certain animals live much longer than other/because of lipid reordering not because of intense DNA repair or redox changes or something else. The fact that the mitochondrias are 'kept' pristine is a major reason why these animals live much longer : They Avoid Damage altogether to their mitochondrias - and especially to the mitochondrial DNA; a major cause of aging (mitochondrial DNA damage) By having mitochondrial lipidome reordering). Avoiding damage is much better/powerful strategy (near 0 damage) than incuring damage and trying to repair it in a mop up/catch up game (it's game we lose at/at a certain point the balanced is tipped towards More Damage than Repair Can Make; thus 'aging').
A study between a 5 year old clam and 500 years old clam MLSP (just a 100 times older, Artica Islandica from Iceland shores), demonstrated that the ultra long-lived clam at very 'protected' mitochondrial membranes that were 'intact' and kept that way for a very long time.
Thei membranes were more saturated (less peroxidizable), thus much less mPTP would have beeng going on over the years, so they had an 'kept' mitochondrial DNA (for we have to understand that it is the PUFA (polyunsaturated fatty acids) lost through mitochondrial ROS that create these chain of lipoperoxydation just close-by to the Complex I and III in ETC - which happens to be right next to the mitochondrial DNA. Thus, the mtDNA is 'spared' in these ultra-long lived animals and they avoid damage their altogether/it just does not manifest/reach the mtDNA. While in the 5 year old clam, it was obvious, very quick loss of redox, rapid rise of damage markers (TBARS, MDA, lipoperoxidation chains, carbonyls, protein damage, etc) in a quick space of time. It's actually impressive because you could really see 'in time' and see that the short lived quahog reached to 100% damage and died; while the long-lived one reached 100% - but ultra-slowly; It was the exact same 100% (total damage incurred) in both...but the long-lived was dramatically slowed accrual (orders of magnitude).
I hope they can control this mPTP problem and we can keep our cytochrome inside our mitochondrias. I understand sometimes pore opeining is important (like killing cancer cells through opening their specific mitochondrial pores), but for healthy cells it is a huge problem.
Just my 2 cents.
It's always interesting reading your posts CANanonymity - one thing to add from the study I linked to: metabolic rate and stability of MtDNA weren't correlated (or only very weakly/indirectly), so in this case I don't think that the link between higher metabolic rate and higher MtROS is warranted; yes there may be higher ATP production, but this doesn't always lead to higher MtROS, probably due to greater efficiency and the other things you mentioned. In this case metabolic rate = MTOR and a higher rate of (premature) cellular senescence, which in most (but not all) cases is independent of the health of the mitochondria.
One other thing - calorie restriction and certain AMPK activators promote mitochondrial fusion, so this is mimicking what those long lived individuals did, namely hiding MtDNA mutations in individual mitochondria through sharing DNA with others. But although this kept some ATP going there is a trade off, as promoting fission instead would temporarily reduce mitochondria numbers (and ATP production) as the bad ones underwent mitophagy, but the remainder would have less damage. This is probably why those who exercise intensely have such a healthspan benefit.
Hi Mark !
Thanks for that, it's also very great reading you too ! It's true there are definate shades of grey and as you said, mtROS and metabolic rate is not a 1:1 thing; and always correlative/or causative even. That's why there is the norm and there are outliers who defy these norms (like long-lived animals whom should technically be dead (if applying the rule of the norm) but aren't/exception to the rule). mtROS can be quenched or rendered nearly inconsequential in long-live animals even if they have faster metabolism. For the rest of the animals, it's a 'trend' and metabolism speed is in correlation to lifespan. But there can be intraspecie differences (one individual of the same specie can liver longer than another/like for example a same quahog whom depending onthe area/environment it lives can live long or short life), so as said it is not set in stone.
What I am wondering is how much does mtDNA damage ties in with cell cycling and replicative senescence - I am almost certain that more mtDNA damage will accelerate replicative senescence (for this manifests as apmlified telomere loss- which means less cell cycle roudns available/thus quicker replicative senescence). But, how much impact or specification is there on this replicative problem, it's why it is diifcult to untangle consequential from non-consequential/or let's say 'quenched/nullified' damage. In seems there is no one single answer and it depends on the species' genetic adaptations that can either overcome this or not.
It's interesting that mtDNA mutations 'hiding' by sharing it in between the mitochondrias could be a sort of evolved mechanism trick to hide this mtDNA mutation burden with age and thus render it inconsquential or less consequential on the mitchondria's stability and ATP output capacity (by hiding it when they fuse). It would make a lot sense. Perhaps, also, a certain synergistic effect when there is a mass of mitochondrias rather than separated ones (kind of like the adage that 2 heads are better than one).
True about the exercise benefits being strong on the mitochondrial dynamics and improving mitochondrial ATP output. I had read that exercised people (after a year or so) had increase telomere length (this means exercise activates telomerase, a not so small detail),
they about 300-400 bp (telomeric DNA base pairs) increase; which means more replicative 'time' (roughly about 7-10 years human life extra, 5000 bp (5 Kb DNA) = 100 years; 500 bp = 10 years).
Hi CANanonymity,
If you don't mind me speculating - I think the reason that mitochondria are so fundamental to determining MLS is because they have this terrible trade off to make - fuse and produce more ATP, or fission and allow mitophagy to detect low membrane potential and 'eat' the fissioned mitos that are small enough to swallow. Clearly in aging ATP production is trumping mitophagy, and increasingly sick mitos are using the transition pore to 'let off steam'. When this ROS is bad enough to seriously damage nDNA it triggers apoptosis.
This will certainly affect telomeres and shorten the time to Replicative senescence but I think the main culprit is probably the direct apoptosis.
I see this mito driven aging as being separate and complementary to TOR driven (premature) senescence. Again I am speculating but appears to fit the data I have seen.