The celebrated Dr. Ian Malcolm famously said, 

“Life, uh, finds a way.”

And indeed — nature has had the luxury of several millennia to refine the plans of life as we know it, including backup plans should something go wrong. Mitochondria are no exception. Generating energy is vital for cell survival, making it a top priority. Furthermore, mitochondria are crucial for regulating cell metabolism, calcium homeostasis, and apoptosis. When mitochondria malfunction, it can lead to various diseases such as neurodegenerative disorders, metabolic issues, heart problems, cancer, and aging. Consequently, preserving mitochondrial function is crucial for maintaining cellular health and normal physiological processes.

Mysteries of the Mitochondria

Mitochondrial biology is so multi-faceted and nuanced, especially when things go wrong. As the mitochondria are important sources of reactive oxygen species (ROS) just through basic function, they’re also the primary suspects when oxidative stress gets out of hand. Despite this, other aspects of mitochondrial quality control and their links to aging are poorly understood. In this article, we will review the roles of the mitochondrial permeability transition pore (mPTP) and the mitochondrial unfolded protein response (UPRmt) necessary for homeostasis and optimal mitochondrial health.

What is the Mitochondrial Permeability Transition Pore (mPTP)?

The mitochondrial permeability transition pore (mPTP) is a protein complex found in the mitochondria, specifically in the inner mitochondrial membrane. This feature is fundamental in regulating general mitochondrial function and programmed cell death. Research on the mPTP has been around for nearly 50 years, where it was first described to occur under elevated calcium levels (1). Opening of the mPTP with calcium overload triggers the release of apoptotic factors and elevated reactive oxygen species (ROS), eventually activating cell death pathways (2, 3). Pore opening unleashes a cascade of changes: 1) mitochondrial swelling, 2) membrane potential collapse, and 3) uncoupling of oxidative phosphorylation, and 4) apoptosis (4, 5). Transition pore dysregulation is implicated in normal aging and aging-associated diseases (6, 7), especially for metabolically-demanding organs such as the heart, (aged human) muscle (8), brain, and liver. For example, aging muscles have reduced ATP synthesis, dysregulated calcium homeostasis, and increased mPTP opening (9).

While counterintuitive, partial opening of the mPTP may be a way to relieve some pressure (10). This triggers the release of mitochondrial ROS and calcium, which act as signals to the nucleus, prompting the activation of protective mechanisms boosting antioxidant systems, increasing mitochondrial biogenesis, and starting the mitochondrial unfolded protein response (UPRmt).

The Mitochondrial Unfolded Protein Response (UPRmt) for Damage Control

As another failsafe mechanism, the mitochondrial unfolded protein response (UPRmt) coordinates a collection of chaperones and proteases dispatched for mitochondrial recovery. When mitochondria experience protein misfolding or accumulation due to stressors like oxidative damage (just one aspect of mitochondrial dysfunction), the UPRmt is activated to restore protein quality control.  This transcriptional reaction promotes protein folding, limits protein import, and reduces protein translation.

At the molecular level, UPRmt activation changes the mitochondrial landscape; the network becomes fragmented, mitophagy happens, and ATP production is compromised (11). But it’s not quite that straightforward anymore. Initially uncovered in worms, studies using mutants with impaired mitochondrial function lived longer with activated UPRmt (12). This finding has been further supported by research in flies and mice (13). The UPRmt can be viewed as a hormetic mechanism, prolonging lifespan despite mitochondrial dysfunction. Interestingly, brief activation of the UPRmt during development can confer long-lasting protective effects and extend lifespan, while prolonged or excessive activation may have the opposite effect, shortening lifespan (14). 

The UPRmt is especially dynamic during aerobic exercise of skeletal muscle (of aged mice). As expected, aging reduced mitochondrial protein levels and lower UPRmt markers. But upon physical training, mitochondrial gene expression was increased and overall function was improved. Furthermore, UPRmt was also activated which correlated with maintenance of mitochondrial function in spite of aged muscle status. This ultimately translated to physiological improvements of reduced total body mass/fat mass content and positive running tests (15). Elevated UPRmt inhibits muscle cell senescence in aged mice, protecting against age-related muscle loss that leads to sarcopenia (16, 17). 

Bottom line: get active! It’s one of the easiest ways to boost UPRmt pathway activation to reverse age-related decline and keep mitochondria happy and healthy.

Key Takeaways

The mitochondria — also called the “great communicator of the cell” — remain elusive, despite mitochondrial dysfunction being a classic hallmark of aging. While there’s solid evidence backing up the idea that mitochondrial-derived oxidative stress plays a role in aging, other aspects of mitochondrial [mal]function, like the mitochondrial permeability transition pore and unfolded protein response, are gradually being recognized as parts of the aging process.

The mitochondrial permeability transition pore (mPTP) and mitochondrial unfolded protein response (UPRmt) are both pivotal for mitochondrial function and overall longevity. New research highlights how the intricate regulation of mPTP activity and the UPRmt process are at the nexus of both keeping cells safe from aging and disease, as well as speeding up aging and causing age-related degenerative diseases. Future research will no doubt further our understanding of mitochondrial stress response and aging.
For now, at the physiological level, improving mitochondrial function can be achieved through various lifestyle interventions such as consistent exercise, eating a balanced diet, intermittent fasting, and incorporating supplements that have been shown to aid mitochondria, like those ingredients found in NOVOS Core. By incorporating these good practices, you can optimize mitochondrial function, reduce oxidative stress, and support overall longevity and healthy aging.

Matilde Miranda

Matilde Miranda, PhD is a seasoned molecular biologist with a fascination for the cutting-edge research happening in skin/longevity fields. She received her doctorate from the University of California, Los Angeles, and then pursued a postdoctoral appointment at the University of Tokyo. She has previously worked on projects encompassing G-protein-coupled receptor signaling in hair follicle stem cell maintenance, and the role of DNA damage in hair loss and skin aging. Skin care is a personal and professional interest of hers, as you can often find her optimizing skincare routines, evaluating popular products, and exploring every cosmetics aisle across the world.

References

1. https://pubmed.ncbi.nlm.nih.gov/38751/
2. https://pubmed.ncbi.nlm.nih.gov/19265700/
3. https://pubmed.ncbi.nlm.nih.gov/37174672/
4. https://pubmed.ncbi.nlm.nih.gov/10393078
5. https://pubmed.ncbi.nlm.nih.gov/26517192/
6. https://pubmed.ncbi.nlm.nih.gov/29888494/
7. https://pubmed.ncbi.nlm.nih.gov/33418876/
8. https://pubmed.ncbi.nlm.nih.gov/24371120/
9. https://pubmed.ncbi.nlm.nih.gov/25726361
10. https://pubmed.ncbi.nlm.nih.gov/28758328/
11. https://pubmed.ncbi.nlm.nih.gov/24930971/
12. https://pubmed.ncbi.nlm.nih.gov/11709184/
13. https://pubmed.ncbi.nlm.nih.gov/23698443
14. https://pubmed.ncbi.nlm.nih.gov/24243023/
15. https://pubmed.ncbi.nlm.nih.gov/37109535
16. https://pubmed.ncbi.nlm.nih.gov/27127236
17. https://pubmed.ncbi.nlm.nih.gov/32173728/