8 Ways to Increase Mitochondrial Biogenesis

Just 1% faster. Just 1% stronger. These are the kinds of gains elite athletes strive for to be just .01 second faster than their competition. But even if you are just a weekend warrior (trying to not get injured in this week's softball game), the better tuned your internal metabolic system is at making energy, the faster, stronger, and less prone to injury you will be too. 

Energy metabolism depends on a key cellular organelle, the mitochondria. They work as the cell power plant, relentlessly providing energy in (almost) every cell of our body via oxidative phosphorylation (OXPHOS) and the electron transport chain (ETC). You have quadrillions of mitochondria in your body. Yes, quadrillions! 

Is there a way to enhance their energy production? OF COURSE! Increasing the number and mass of mitochondria in the cell will improve your metabolic capacity. In this article, we are going to dive into 8 ways you can enhance mitochondrial biogenesis. 

But first...

What is mitochondrial biogenesis?

Healthy cells need a balanced mitochondrial pool: a controlled mitochondrial mass and function imply good energy and metabolism for other essential processes. Mitochondria are particularly affected by aging since they are the cell’s most significant source of oxidative stress. For this reason, regulating mitochondrial regeneration becomes essential for improving performance.

You inherit your mitochondria from your mother (so blame her) and during cell growth, the balance of two processes maintains mitochondrial homeostasis: the generation of new mitochondria, or mitochondrial biogenesis, and the recycling of damaged mitochondria, or mitophagy.

Master genetic regulators are responsible for this fine-tuning. These are DNA-binding molecules expressed in response to an external stimulus, which are translocated to the nucleus and activate specifically related genes. Even though mitochondria have some degree of independence when it comes to gene expression, 60-70% of mitochondrial proteins are codified in nuclear DNA and later internalized in the organelle itself. Targeting signals in these pre-proteins redirect them to their destination: outer or inner membranes and intermembrane spaces.

The biogenesis of new mitochondria comprises the recruitment of pre-existing mitochondria and fragmentation via a process called fission, ensuring constant renewal of the mitochondrial pool. The master regulator for the process is the peroxisome proliferator‐activated receptor‐γ coactivator (PGC)‐1α. PGC‐1α activates the transcription of mitochondrial DNA (mtDNA) via transcription factor A (TFAM). It regulates protein expression in response to interaction with several signaling pathways (SIRT1, AMPK, CaMK, CREB) related to cellular growth, differentiation, temperature stress, and energy metabolism.

Here are some ways to boost mitochondrial biogenesis:

Exercise 

Endurance athletes are efficient energy producers. Not only do they have an increased mitochondrial volume (up to 40-50% more) and higher OXPHOS capacity [1,2], but their mitochondria also display a particular structure.

Nielsen et al. [3] found that mitochondria from endurance athlete’s leg muscles presented an increased amount of inner membrane (cristae), providing an improved surface for the ETC and augmented oxygen uptake. There are actually some really cool mathematical models suggesting that a growing cristae optimizes ATP production by minimizing the distance between ADP-ATP transforming sites [4]. 

Although these results were obtained from high-performance athletes, even a single bout of exercise can help our body gain extra metabolic capacity in the muscles [5].

Recent findings suggest that high-intensity training bouts, such as HIIT and SIT modalities, are very efficient at promoting mitochondria biogenesis. Only 3 hours after exercise (4 × 30-second bursts of all-out maximal intensity cycling), researchers found increased levels of PGC-1α in the cell nucleus, coinciding with increased mitochondrial gene expression [6].

After 6-7 HIIT or SIT sessions, mitochondria content can rise up to 25-35% [7,8]. Make sure to apply progressive increments in intensity to improve mitochondrial content [9]. Maintaining the same exercise intensity and duration may cause a plateau after 5 days of training [10]. In short, don't make your exercise boring! 

Ginger Extract 

Keep adding that extra spice to your tea! Ginger extract is widely used in Mediterranean and Asian food. A recent study found that mice fed with 2 g per 1 kg of ginger extract have an increased number of mtDNA copies in the muscles and liver as well as higher OXPHOS-related proteins and mitochondria abundance in the muscle, liver, and brown adipose tissue [11]. The active compound, 6-gingerol, could become the next super dietary ingredient.

Photobiomodulation

Photobiomodulation (PBM) is a potent cellular therapy that uses red or near-infrared (NIR) light to promote cell proliferation, ATP production, control of inflammation and pain, formation of new muscle fibers, and acceleration of generation and repair of new blood vessels and tissues.

At a cellular level, red light stimuli in complex IV of the ETC energizes the metabolism in neurons and muscles via induction of complex activity [12].

Recent studies in muscle tissue have also proved PBM’s ability to activate the biogenesis machinery via PGC-1α expression and other key regulators (SIRT1) after 4 days of NIR light exposure (dual wavelengths of 808+980 nm) [13].

Even though PBM’s role in sports is discussed depending on the discipline, creative applications of the technology could modulate mitochondrial activity, enhancing athletic performance and improving post-exercise recovery.

The best part is that there is no potential secondary effect regarding heat or toxic dependency. The FDA has already approved the treatment for wound healing and joint pain and it is still being researched for multiple other conditions. It’s worth exploring, so maybe it’s time to book a red-light therapy session at your nearest wellness center!

Calorie Restriction

Calorie restriction is the strongest intervention to reduce mitochondrial leakage of reactive oxidative species (ROS) and optimize body energy consumption [14]. It has been shown to increase life expectancy and improve the aging rate in several species (from yeasts to mammals). Surprisingly, a low-calorie diet in humans also triggers mitochondrial proliferation. Biogenesis regulators (PGC-1α, Tfam, eNOS, and SIRT1) and mitochondrial content were increased in the muscles of non-obese patients subjected to a calorie-restricted diet compared to the control group [15]. Similar results were obtained in mice fed with a ketogenic diet [16], a diet consisting of low carbohydrates, high-fat content, and moderate amounts of protein. This type of diet induces a shift in metabolism, making your body super-efficient in burning fat instead of carbs (ketosis). A keto diet stimulates mitochondrial abundance and performance, and also helps to regulate antioxidant mechanisms.

Muscle Massage

There is nothing better than having an excuse for a massage! A 2012 study found that PGC-1α levels elevated in the nucleus several hours after a muscle massage, indicating additional mitochondrial formation. Massages generate a signaling cascade from mechanical stress sensors in the muscle cells and has proven to accelerate healing through the reduction of inflammation [17].

Heat 

Animal studies have shown that repeated exposure to mild heat stress may upregulate PGC-1α expression as well as expression of mitochondrial OXPHOS subunits. Exposure to temperatures around 40 °C for 5 days confirmed increased protein levels and mtDNA copy number. Repeated sessions of pulsed shortwave therapy (PSWT) (2 hours daily for 6 consecutive days) induced expression of PGC-1α and mitochondrial ETC protein complexes I and V [18].

Additionally, heat shock proteins (HSPs) 70 and 90 were also increased by up to 45%. These enzymes are produced in response to stress and assist in protein folding and complex assembly.

Animals that over-express HSPs usually present higher mitochondria numbers and enhanced OXPHOS capacity. PSWT is a safe technique used in rehabilitation clinics as an injury recovery tool, so it would not be difficult to escalate for further metabolism research. If not, you can always try sauna sessions or hot yoga classes!

Carvedilol 

Carvedilol, a heart medication used in heart failure and for high blood pressure, protects mitochondria from stress and fosters the production of mtDNA and protein contents via PGC1-α activation, including cytochrome c and ETC complex IV [19]. In addition, it increases mitochondrial mass and respiratory rate in epithelial cells. Be careful though! Beta-blockers like carvedilol are considered doping in professional athlete competitions depending on the discipline and might get you disqualified. DYOR!

Interestingly, several glucose-lowering drugs (Empagliflozin, Alogliptin, Metformin, Pioglitazone) also have an effect on mitochondrial biogenesis. Clinical and experimental studies have described the pleiotropic action of these drugs, including stimulation of mitochondrial proliferation through PGC1-α-TFAM activation [20].

Polyphenols

Natural compounds found in green tea, yerba mate, and wine promote cell pathways for mitochondrial regeneration and homeostasis. Resveratrol is a compound found in grapes, red wine, berries, tomatoes, peanuts, soy, and Itadori tea, a traditional herbal remedy used in China and Japan for heart disease. It seems a healthy scavenger hunt in Chinatown can have additional benefits!

Resveratrol seems to activate PGC-1α via SIRT1, promoting mitochondria biogenesis by initiating the AMP protein kinase (AMPK) pathway with a direct impact on cell metabolism [21]. Benefits in multiple models of neuropathies such as Alzheimer's, Down syndrome, cognition impairments, and aging via modulation of the SIRT1-AMPK-PGC1-α pathway have proven the compound effective for mitochondrial content regeneration. In fact, our star molecule methylene blue (MB) has been proven to exert a similar effect in hepatic cells [22]. Due to its good permeabilization to the brain, it can also be used as a treatment for these pathologies. MB has already been used as a treatment in clinical trials for methemoglobinemia, ischemic reperfusion injury, and cyanide poisoning.

Conclusion

The mitochondrial cellular pool must constantly regenerate and recycle to deliver energy efficiently. Fortunately, mitochondria display amazing plasticity and adaptability to changing conditions. We have seen that multiple transcription factors sense the external media, enhancing the production of mitochondrial proteins and genes in response to different stimuli.

Even though there is still much to be confirmed by further research, implementing one or several of these interventions could dramatically change the quality and quantity of the quadrillions of mitochondria for the better... and that means you'll have more energy, less brain fog, more resilience, and feel all around more awesome. Pretty cool, eh? 

References

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