Pandora’s Box: Mitochondrial DNA Release Drives Senescence Signature

NOVOS Short Report: Recent Advances in the Science of Longevity

This article provides an overview of a study published in Nature titled “Apoptotic stress causes mtDNA release during senescence and drives the SASP”, which explores the relationship between apoptotic stress, mitochondrial DNA (mtDNA) release during cellular senescence, and the senescence-associated secretory phenotype (SASP). 

Optimal mitochondrial health is a reflection of general health. These famous organelles are very similar to batteries — and batteries are no good when they cannot provide enough power or cannot hold a charge to sustain a device. In the same vein, mitochondrial dysfunction can be generally defined as a reduction in energy production, reduced membrane potential, and increased generation of harmful free radicals.

The mitochondrial state is closely interlinked with the senescence state. Cellular senescence can be described as a stable cell cycle arrest, where cells exist in a type of “limbo” between functional and damaged. Senescent cells are present from before birth, and regulated senescence is necessary for proper development and immune response (1). However, in an uncontrolled setting — like during chronic injury or disease — senescent cells begin to disrupt their healthier neighbors by secreting pro-inflammatory factors, collectively known as the senescence-associated secretory phenotype (SASP). A vicious cycle of inflammation is then triggered — and, if left unchecked — can go on to damage the microenvironment, leading to disease and aging.

How Are Mitochondrial Dysfunction and Senescence Related?

As you may already know, mitochondrial dysfunction is a key hallmark of aging, as is senescence (2). Indeed, mitochondria of senescent cells undergo structural changes (3) that affect their function. Furthermore, cellular senescence also alters mitochondrial dynamics, as observed with elongated “giant” mitochondria upon induction of senescence-associated pathways (4). 

The elimination of mitochondria from senescent cells was been shown to reverse senescence (5). Another team detected the presence of mitochondrial-derived peptides (MDPs) in the cytoplasm of senescent cells as a component of the SASP (6). These discoveries paved the way for proposing that altering mitochondria may be promising for the development and optimization of anti-senescence therapies. Kind of a “two bird, one stone” situation.

This recent article (7) further explores the connection between mitochondrial dysfunction and senescence propagation, highlighting why mitochondrial leakage from aged/damaged cells causes inflammation, and what interventions can be developed to curb the deleterious damage of the SASP for healthy aging.

Mitochondrial Dysfunction Influences Senescence State

Mitochondria are rightly recognized as the powerhouses of the cell.  But there’s a lot more to them besides supplying cellular energy to our hardworking cells. Mitochondria are ancient yet highly dynamic organelles, containing their own (small) genome that is vital to sustaining energy demand, oxidative stress regulation, and controlled cell death (apoptosis). Mitochondria are also important hubs for inflammation, making their connection to a newer hallmark of aging, “inflammaging” (8).

Bridging the Mitochondrial DNA-SASP Gap

This groundbreaking study, co-led by Dr. Stephen Tait (University of Glasgow) and Dr. João Passos (Mayo Clinic), found that aged cells (or cells that received cancer therapy) exhibited leaky mitochondria. One feature of mitochondrial leakage is the release of mitochondrial DNA (mtDNA). This is formally known as mitochondrial outer membrane permeabilization (MOMP) and resembles what naturally occurs during apoptosis. However, in a senescence background (triggered by radiation), leaked mtDNA did not induce apoptosis, in a phenomenon known as minority mitochondrial outer membrane permeabilization (miMOMP). This led to the hypothesis that miMOMP is a driver of the SASP, where instead of rapid cell death, miMOMP can trigger a pathway known as cGAS-STING for a shift towards the SASP response.

The cGAS-STING Pathway is Triggered by mtDNA Release 

The cyclic GMP-AMP synthase (cGAS) – stimulator of interferon genes (STING) pathway is central to mediating inflammation through its immune sensing of DNA (9). While DNA is primarily known for carrying genetic information, it can also be used as a tracer for signaling to the host immune system to respond to foreign (often pathogenic) DNA. Infection, oxidative stress, and mitochondrial dysfunction can all disrupt mitochondrial integrity, triggering an immune response, as mtDNA in the cytoplasm is not a normal characteristic of proper cell function. Activation of cGAS-STING with mtDNA ultimately results in apoptosis, a mechanism of non-inflammatory cell clearance. Abnormal cGAS-STING activity is a pattern in cellular senescence, most prominently as a SASP component (10). However, the direct connections between cGAS-STING and “inflammaging” require further study.

BAX/BAK Macropores Facilitate mtDNA Leakage and SASP

The release of mtDNA can occur through pro-apoptotic BAX/BAK macropores (11). When MOMP is activated, BAX/BAK-mediated pores widen, facilitating mtDNA release. This is interpreted as a non-inflammatory form of cell death, “immunologically silent” to not trigger a widespread response. The paper co-written by Dr. Stephen Tait and Dr. João Passos provides more novel findings by reporting that BAX/BAK formed oligomers in senescent (but not proliferating) cells and promoted the SASP in cell lines and mouse samples.

Reducing Mitochondrial Leakage for Longevity

Lastly, the scientists found that by blocking mtDNA leakage, the SASP was reduced. Pharmacological inhibition of miMOMP with the small molecule BAI1 was effective in suppressing several SASP factors in senescent fibroblasts, prompting testing in an aged mouse (20 months old) setting. After several months of treatment, neuromuscular coordination readouts like balance and grip strength were improved. Additionally, the base healthspan in elderly mice was increased, but the lifespan remained unaffected. Treated mice also displayed improved bone microarchitecture, with increased resistance to torsion, in addition to a slight decrease of pro-inflammatory markers of the SASP. BAI1 was able to cross the blood-brain barrier to provide senomorphic effects, reducing the expression of some inflammatory factors. Importantly, treatment reduced senescence markers in microglia and oligodendrocytes, which have been shown to be the main senescent cell targets in the aging brain. While this paper only tested aged mouse bone and brain tissues, we are hopeful this senescent cell clearance is widespread for rejuvenating other tissues that fall victim to senescent cell burden.

Key Takeaways

• Mitochondrial DNA is released into the cytosol during senescence
• Mitochondrial permeabilization promoted inflammation in aged and damaged cells
• Blocking mtDNA leakage improved musculoskeletal outcomes and healthspan
• Blocking mtDNA leakage inhibited the SASP in mice
• Blocking mtDNA leakage blocked inflammation, providing new avenues for aging and cancer treatments

This paper unveiled more ties between mitochondrial dysfunction and cellular senescence, with mtDNA, cGAS-STING, and the SASP being the main characters. This work is an exciting major step towards developing mitochondrial therapies that can also target senescence pathways without a large immune response.

At NOVOS, part of our mission is to make the latest achievements and discoveries in longevity science accessible to all. We are committed to continually sharing updates and developments in this exciting field.

References

1. https://pubmed.ncbi.nlm.nih.gov/24238961/
2. https://pubmed.ncbi.nlm.nih.gov/23746838/
3. https://pubmed.ncbi.nlm.nih.gov/19528227/
4. https://pubmed.ncbi.nlm.nih.gov/16883569/
5. https://pubmed.ncbi.nlm.nih.gov/26848154/
6. https://pubmed.ncbi.nlm.nih.gov/29886458/
7. https://pubmed.ncbi.nlm.nih.gov/37821702/
8. https://pubmed.ncbi.nlm.nih.gov/36599349/
9. https://pubmed.ncbi.nlm.nih.gov/33833439/
10. https://pubmed.ncbi.nlm.nih.gov/28533362/
11. https://pubmed.ncbi.nlm.nih.gov/30049712/