When they aimed the new imaging system at cells treated with low-dose apoptotic agents, they unexpectedly found that “mitochondrial outer membrane permeabilization” (MOMP), which signals rapid cell death, occurred at extremely low levels, but Does not cause cell death[1]。
Cells survive normally, no intermediate states (pixabay)
You must know that in previous knowledge, the outer membrane permeabilization of all mitochondria in a cell occurs simultaneously: either all mitochondria undergo outer membrane permeabilization and then undergo apoptosis; or none of the outer membrane permeabilization occurs, Cells survive normally, with no intermediate state[2]. Therefore, this discovery by the Tait team rewrote the common understanding at the time. They named this phenomenon “minority mitochondrial outer membrane permeabilization” (minority MOMP).[1]。
What worries Tait and his colleagues is that they also found that a small number of mitochondrial outer membrane permeabilization occurs, which can lead to DNA damage and promote genome instability, cell transformation and tumorigenesis.[1]. To put it simply, if the apoptosis program is initiated relatively thoroughly, the cells will die quietly; if the apoptosis program is not initiated completely, the cells will become cancerous. From this point of view, the process of promoting apoptosis is also “one body and two sides”, which can both prevent cancer and promote cancer.
Discoveries in 2015 (online photo)
This discovery by Tait’s team attracted the attention of João F. Passos’s team at Miaoyu Medical International in the United States.As an expert in the study of cellular aging, Passos and his team have confirmed that mitochondria play a key role in the aging process of cells, and that mitochondria may be an anti-aging target.[3]。
So the Passos team wanted to know whether permeabilization of the outer membrane of a small number of mitochondria was behind the aging process; and if so, whether it might be possible to find anti-aging and cancer drugs. These issues prompted the cooperation between the Passos team and the Tait team.
Recently, the Tait team and the Passos team published a major research result in the top journal “Nature”. They discovered for the first time that the permeabilization of the outer membrane of a small number of mitochondria is a feature of cellular aging, and revealed that the permeabilization of the outer membrane of a small number of mitochondria promotes aging. Mechanisms[4]. What’s more, they also found that inhibiting mitochondrial outer membrane permeabilization extended the healthy lifespan of mice.
It is worth noting that this study also suggests that cell senescence and apoptosis, two different cell fates, actually use similar mitochondrial regulatory mechanisms. This also means that the three different fates of cells, namely senescence, canceration and apoptosis, originate from the same root. This has important implications for the prevention and treatment of aging and related diseases (such as cancer).
Screenshot of the paper’s homepage (online image)
To observe whether there is a small number of mitochondrial outer membrane permeabilization in senescent cells, Passos’ team used 3D structured light illumination microscopy to observe proliferating or senescent human fibroblasts.
Sure enough, they found a small number of mitochondrial outer membrane permeabilization phenomena in senescent cells. In addition, they also found that the pro-apoptotic protein BAX on the mitochondrial membrane was activated and the levels of cytoplasmic mitochondrial DNA (mtDNA) increased. These results confirm that mitochondrial outer membrane permeabilization does occur in senescent cells.
Mitochondria are leaking (Internet picture)
Given that the senescence-associated secretory phenotype (SASP) is a typical feature of cellular aging, Passos’ team investigated whether permeabilization of the outer membrane of a small number of mitochondria could drive SASP.
They found that after the pro-apoptotic protein BAX/BAK, which is necessary for mitochondrial outer membrane permeabilization, was deleted, mtDNA was no longer released, and common expressed genes related to SASP were reduced. This shows that mitochondrial outer membrane permeabilization indeed regulates SASP.
As for the mechanism behind it, their observations show that under the stimulation of external conditions, mitochondria in aging cells reduce mitochondrial fragmentation through excessive fusion; in this case, a small amount of mitochondrial mitochondrial outer membrane permeabilizes the released mtDNA It will activate the cGAS-STING signaling pathway, thereby driving the occurrence of SASP. Simply put, it is the mitochondrial dynamics of senescent cells that regulate SASP induced by permeabilization of the outer membrane of a small number of mitochondria.
Mechanism diagram (network diagram)
At this point in the research, you may have a question: Why does mtDNA produced by apoptosis not cause SASP, but instead, a small number of mtDNA released by permeabilization of the outer mitochondrial membrane drive SASP?
Regarding this issue, the Passos team has also done some exploration.
In fact, during the process of apoptosis, mtDNA is also released, but apoptosis will lead to the activation of caspase, which will inhibit mtDNA from activating cGAS-STING signal and will not cause immune response.[5,6]. Therefore, apoptosis is silent and does not drive SASP.
However, the Passos team found that during the process of cellular senescence, caspase activation caused by permeabilization of a small number of mitochondrial outer membranes is not enough to inhibit the activation of cGAS-STING signaling, thus inducing SASP.
Comparison of proliferating cells (Prol) and senescent cells (Sen) (network image)
After revealing the underlying mechanism, the final question faced by the Passos team was whether inhibiting mitochondrial outer membrane permeabilization could alleviate aging.
They treated 20-month-old mice with the small molecule inhibitor BAI1 of BAX for 3 months and found that the mice’s age-related neuromuscular coordination was improved, their forelimb grip strength was also improved, and age-related weakness symptoms were reduced. Development was also slowed.
Notably, BAI1 treatment extended the healthspan of aged mice, and BAI1 can also cross the blood-brain barrier and reduce inflammation and cellular senescence in the aging brain.
Overall, this study by Tait’s team and Passos’ team shows that mitochondrial outer membrane permeabilization is also a driver of aging. Given that mitochondrial outer membrane permeabilization is also a driver of cancer, drugs that inhibit mitochondrial outer membrane permeabilization may be universal drugs against aging, cancer, and other aging-related diseases.
references:
[1].Ichim G, Lopez J, Ahmed SU, et al. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol Cell. 2015;57(5):860-872. doi:10.1016/j.molcel.2015.01.018
[2].Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol. 2000;2(3):156-162. doi:10.1038/35004029
[3].Correia-Melo C, Marques FD, Anderson R, et al. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J. 2016;35(7):724-742. doi:10.15252/embj.201592862
[4].Victorelli S, Salmonowicz H, Chapman J, et al. Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature. 2023. doi:10.1038/s41586-023-06621-4
[5].White MJ, McArthur K, Metcalf D, et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell. 2014;159(7):1549-1562. doi:10.1016/j.cell.2014.11.036
[6].Rongvaux A, Jackson R, Harman CC, et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell. 2014;159(7):1563-1577. doi:10.1016/j.cell.2014.11.037
2023-12-17 11:35:54
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