Mitochondrial Damage and Dysfunction: A Pathway to Aging

Mitochondria are the key organelles for producing the energy that keeps the engine of life running. At the molecular level, mitochondrial health directly impacts the efficiency of oxidative phosphorylation to produce ATP. This high-power molecule is constantly generated through dedicated mitochondrial processes and used to fuel all sorts of activities, big and small — from making new DNA to making it across a finish line.

Understanding Mitochondrial Dysfunction

Scientists have long known that mitochondria play pivotal roles in the aging process, with mitochondrial dysfunction being a major hallmark of aging (1). Keeping mitochondria in good shape is fundamental for keeping balance in health. When this balance is lost, mitochondrial damage and dysfunction can open the floodgates of disease.

Mitochondrial dysfunction is associated with a wide range of health conditions, including neurodegenerative diseases, metabolic disorders, cardiovascular diseases, and aging. Mitochondrial dysfunction is an umbrella term to describe the suboptimal function of cellular energy production. What exactly goes wrong? Below are four categories of changes that occur.

Membrane Potential Disruption

Previous research has shown that mitochondrial membrane potential is lower in aged cells (2, 3). The direct mechanism underlying this phenomenon is still poorly understood, but many believe that oxidative stress and mitochondrial uncoupling play a role. Mitochondrial uncoupling is the process where the normal coupling between the electron transport chain (ETC) complexes and ATP synthesis step is disrupted. As a result, the proton gradient (voltage potential) normally generated across the inner mitochondrial membrane is absent, resulting in the release of energy as heat, instead of in the form of ATP molecules. This decrease in polarization can lead to mitophagy, or clearance of defective mitochondria. If drops in membrane potential suddenly occur, oxidative phosphorylation (ATP production) ceases (4), setting off a string of alarms to trigger apoptosis (5). Thankfully, promising research in nematodes revealed that increasing membrane potential during adulthood can stave off dysfunction, aging characteristics, and improve lifespan (6).

Oxidative Phosphorylation Disruption

Under physiological conditions, reactive oxygen species (ROS) are a byproduct of mitochondrial ATP production. Our cells have developed antioxidant processes to quench these harmful free radicals, but these systems can become overloaded when there is cumulative damage to mitochondria, allowing ROS to wreak havoc to other macromolecules, especially to sensitive mitochondrial DNA (mtDNA) (7, 8, 9). Loss in respiratory capacity is also a common symptom of senescent cells (10).

Mitochondrial DNA Mutations

Outside of the nucleus, mitochondria are the only other organelles that have their own genome. At a modest 16.6k base pairs longs, mitochondrial DNA (mtDNA) is organized in structures called nucleoids, which lack protective histones normally observed with genomic DNA (11). MtDNA encodes respiratory chain subunits (12) that are assembled for oxidative phosphorylation. MtDNA is unfortunately vulnerable to external damage, so cumulative DNA damage leads to oxidative damage, mutagenic lesions, and impaired repair (13). 

Mitochondrial mutations can then be passed down to the next generation through cell division, and have been shown to accumulate in different tissues during aging (14). This was shown in a mutator mouse model, engineered with a defective DNA polymerase to cause extensively random, progressive DNA mutations that would accumulate during mitochondrial biogenesis (15). The mtDNA mutator mice were born normally but experienced prematuring aging symptoms such as weight loss, reduced subcutaneous fat, heart disease, alopecia, and decreased mobility. This mtDNA mutation overload is therefore associated with tissue dysfunction and organ decline.

Quality Control Disruption

Mitochondrial biogenesis makes “new” mitochondria in response to several inputs such as metabolic demand, cell growth, and stress (16). Coupled with mitophagy, this dynamic crosstalk allows metabolic programming and mitochondrial turnover. During mitochondrial dysfunction, bioenergetics are impaired because of suboptimal ATP synthesis. This progressive decline in homeostasis is very well studied in the brain since it is one of the most energy-demanding organs in the human body, very dependent on mitochondria and cellular respiration. Many neurodegenerative diseases originate through disorders in mitochondrial biogenesis (17). 

Once the mitochondrial network is established, its maintenance is also tightly regulated. Mitochondrial fission and fusion events counteract each other, occurring in response to stress and energy needs. Tipping the scales towards more fission events results in punctate mitochondria and a fragmented network – much like beads; a hyperfused mitochondria network has elongated organelles – much like string. Mitochondrial fission is necessary for appropriate segmentation of organelles during mitosis, but it is also a feature prevalent upon high stress, senescence, and cell death (18). Mitochondrial fusion can often offset low levels of damage via complementation (19); fusion also provides more space for cellular respiration (especially in starvation states) but then has negative impacts upon cellular division and plays a huge role in cancer progression. Yet another impasse; different types of longevity mechanisms vary in their fission/fusion ratios (and in different research organisms!) (20), further strengthening the notion that mitochondrial fission/fusion is context-dependent.

Mitophagy rounds out the rest of mitochondrial turnover. Mitophagy is the process of selectively removing aged and/or damaged mitochondria for targeted degradation. When mitochondrial damage is beyond the point of no return, this can lead to massive programmed cell death or senescence development in an effort to maintain cellular fitness. Insufficient mitophagy and accumulation of swollen, damaged mitochondria in neurons is well-documented in the pathogenesis of Parkinson’s disease (21).

Exploring the Context of Mitochondria and Senescence

Mitochondria are at the crossroads for life and death. So it’s not too surprising to see mitochondrial dysfunction associated with cellular senescence, another big candidate in the hallmarks of aging. Cellular senescence is a stress response where cells undergo a stable cell cycle arrest, metabolic reprogramming, and adopt a secretory mixture of inflammatory signals. Like teaching a bad habit, senescence is not an isolated cell event; neighboring cells will adopt these changes and pass them on. Senescent cells accumulate dysfunctional mitochondria and are resistant to cell death, all while perpetuating a field of oxidative stress and inflammation that of which  a signature is the senescence-associated secretory phenotype (SASP) (22, 23). It’s important to fully consider that dysfunctional mitochondria are not just a trigger but can modulate senescence cell fate and physiology as a whole. Many senolytic and senomorphic drugs being currently developed target mitochondria (and their respective apoptosis program) in order to keep senescence at bay.

Enhancing Mitochondrial Health with NOVOS Core

Mitochondria are dynamic organelles that take on a lot of responsibility in keeping us alive and powering our bodies. But even they need a little bit of support to achieve the hard goal of keeping us in good health. NOVOS Core is a formula backed by longevity experts to tackle all the hallmarks of aging.

Here are some notable ingredients in our supplement that support mitochondrial health:

• fisetin: this flavonoid naturally found in strawberries, apples, grapes (among other fruits/veggies) acts as an antioxidant to protect against oxidative stress and augments mitochondrial biogenesis (24)
• glycine: this amino acid was found to restore mitochondrial function and mitophagy in aging humans (25)
• glucosamine: this ingredient improves mitochondrial membrane potential and protects against mitochondrial-mediated apoptosis (26) 
• pterostilbene: structurally similar to resveratrol, this molecule reduces oxidative stress and increases mitochondrial biogenesis (27, 28)
• calcium alpha-ketoglutarate: as one of the intermediate metabolites necessary for energy production, AKG stabilizes membrane potential and alleviates apoptosis in the presence of oxidative stress (29)
• ginger: the active 6-gingerol has been shown to promote mitochondrial biogenesis and ATP production (30)
• rutin: when given to aged rats, this flavonoid improved antioxidant systems and lowered inflammation (31)

You can read the full list of longevity-promoting ingredients in NOVOS Core and their benefits here.

Key Takeaways

Remember the Ds of mitochondrial dysfunction: impaired membrane potential, increased oxidative stress, low ATP production, and quality control errors lead to progressive mitochondrial damage, culminating in a vicious cycle of degeneration that manifests in disease or even death.

What can you do about it? Supporting your mitochondria through exercise, supplements/healthy diet, good quality sleep, and other longevity practices are some of the easiest ways to improve overall health. 

What do we hope for long-term? That future discoveries will pave the way for deeper insights into aberrant mitochondrial function and for the development of promising therapies to reverse cellular aging and age-associated decline.

References

1. https://pubmed.ncbi.nlm.nih.gov/36599349/
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30. https://pubmed.ncbi.nlm.nih.gov/31369153/
31. https://pubmed.ncbi.nlm.nih.gov/26804783/