*For medical professionals only
In early 2015, Stephen W. G. Tait's team at the University of Glasgow in the United Kingdom reported an unusual discovery.
When they aimed the novel imaging system at cells treated with low-dose apoptostics, they unexpectedly found that "mitochondrial outer membrane permeabilization" (MOMP), which marks rapid cell death, occurred at extremely low levels, but did not result in cell death [1].
You know, in the previous understanding, the outer membrane permeabilization of all mitochondria in a cell occurs synchronously: either all mitochondria undergo outer membrane permeabilization, and then apoptosis; Either no outer membrane permeabilization occurs, and the cells survive normally with no intermediate state[2]. Therefore, this discovery by the Tait team rewrote the common perception 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, leading to DNA damage that promotes genomic instability, cell transformation, and tumorigenesis [1]. Simply put, if the apoptotic procedure is started more thoroughly, the cell dies silently; If the apoptotic process is not started thoroughly, the cell will become cancerous. In this way, the procedure to promote apoptosis is also "two sides of the same coin", which can prevent cancer and promote cancer.
Discovery in 2015
The discovery by the Tait team attracted the attention of Mayo Clinic's João F. Passos team. As experts in the study of cellular senescence, Passos and his team have shown that mitochondria play a key role in the aging process of cells, and that mitochondria may be anti-aging targets [3].
So the Passos team wondered if a small number of mitochondrial outer membrane permeabilization plays a role in promoting aging; If yes, is it possible to find anti-aging and cancer drugs. These issues led to the collaboration between the Passos team and the Tait team.
Recently, the Tait team and the Passos team published a blockbuster study in the top journal Nature, they found for the first time that a small number of mitochondrial outer membrane permeabilization is a feature of cellular senescence, and revealed the mechanism of a small number of mitochondrial outer membrane permeabilization to promote aging [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 the two different cell fate trends of cellular aging and apoptosis actually use similar mitochondrial regulatory mechanisms. This also means that the three different fate outcomes of cell aging, cancer and apoptosis are originally the same root "birth". This has important implications for the prevention and treatment of aging and related diseases, such as cancer.
Screenshot of the first page of the paper
To observe the presence of a small number of mitochondrial outer membrane permeabilization in senescent cells, Passos' team looked at proliferating or senescent human fibroblasts using 3D structured light illumination microscopy.
Sure enough, they found a small number of mitochondrial outer membrane permeabilization in senescent cells. In addition, they found that the pro-apoptotic protein BAX on the mitochondrial membrane was activated, as well as increased levels of cytoplasmic mitochondrial DNA (mtDNA). These results confirm that senescent cells do undergo mitochondrial outer membrane permeabilization.
Mitochondria leak
Given that aging-associated secretion phenotypes (SASPs) are typical of cellular senescence, Passos' team investigated whether a small number of mitochondrial outer membrane permeabilization could drive SASPs.
They found that after deletion of BAX/BAK, a pro-apoptotic protein necessary for mitochondrial membrane permeabilization, mtDNA was no longer released, and SASP-associated common expression genes were reduced. This indicates that mitochondrial outer membrane permeabilization is indeed regulating SASP.
As for the mechanism behind it, the results they observed showed that under the stimulation of external conditions, mitochondria in senescent cells reduce mitochondrial fragmentation through excessive fusion; In this case, a small amount of mtDNA released by mitochondrial outer mitochondrial membrane permeabilization activates the cGAS-STING signaling pathway, which in turn drives the occurrence of SASP. Simply put, it is the mitochondrial dynamics of senescent cells that regulate a small number of mitochondrial outer membrane permeabilization-induced SASPs.
Schematic diagram of the mechanism
At this point in the study, you may have a question: why does the mtDNA produced by apoptosis not cause SASP, but a small number of mtDNA released by mitochondrial outer membrane permeabilization drive SASP?
The Passos team has also done some exploration on this issue.
In fact, in the process of apoptosis, there is also the release of mtDNA, but apoptosis causes caspase activation, which in turn inhibits mtDNA activation of cGAS-STING signaling without causing an immune response [5,6]. Therefore, apoptosis is silent and does not drive SASP.
However, Passos' team found that during cellular senescence, the activation of caspase due to a small number of mitochondrial outer membrane permeabilization was not enough to inhibit the activation of cGAS-STING signaling, and therefore induced SASP.
Comparison of proliferating cells (Prol) and senescent cells (Sen).
After revealing the mechanism behind it, the final question Passos' team faced was whether inhibiting mitochondrial outer membrane permeabilization could alleviate aging.
They treated 20-month-old mice with BAI1, a small molecule inhibitor of BAX, for 3 months and found that the mice had improved age-related neuromuscular coordination, improved forelimb grip strength, and delayed the development of age-related weakness symptoms.
Notably, BAI1 treatment extended the healthy lifespan of older mice, and BAI1 could also cross the blood-brain barrier, reducing inflammation and cellular aging in aging brains.
Overall, this study by Tait's and Passos' teams suggests that mitochondrial outer membrane permeabilization is also a driver of aging. Given that extramitochondrial membrane permeabilization is also a driver of cancer, drugs that inhibit extramitochondrial membrane permeabilization may be generic drugs for anti-aging, anti-cancer, and against other aging-related diseases.
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Bibliography:
[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
The author of this article 丨BioTalker