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8 Ways to Increase Mitochondrial Biogenesis

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 OXPHOS and the 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. 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 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 the 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 ideas to boost your mitochondrial biogenesis!

  1. EXERCISE

Endurance athletes are efficient energy producers. Not only do they have increased number of mitochondrial volume (up to 40-50% more) and higher OXPHOS capacity (1,2), but also their mitochondria 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-s bursts of all-out maximal intensity cycling), researchers could find increased levels of the biogenesis regulator PGC-1α in the cell nucleus, coincidental with increased mitochondrial gene expression (6).

After 6-7 HIIT or SIT sessions, the 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 intensity and duration in your exercise may cause a plateau after 5 days of training (10). In short, don't make your exercise boring! 

  1. 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 2g/kg of ginger extract have an increased number of mtDNA copies in muscle 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.

  1. 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, 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 muscle via induction of the 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.

And 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 is still under research 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!

  1. 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 muscle 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.

  1. MUSCLE MASSAGE

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

  1. 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 h 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, fun!

  1. 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).

  1. 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 see,s a healthy scavenger hunt in Chinatown can have additional benefits.

Resveratrol seems to activate PGC-1α via sirtuin 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 quantify 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? 

Written by: Estafania Urdaniz, PhD 

Edited by: Dr. Scott Sherr

References

[1] Di Donato DM, et al. Influence of aerobic exercise intensity on myofibrillar and mitochondrial protein synthesis in young men during early and late postexercise recovery. Am J Physiol Endocrinol Metab. 2014 May 1;306(9):E1025-32. doi: 10.1152/ajpendo.00487.2013.

[2] Tamura Y, et al. Postexercise whole body heat stress additively enhances endurance training-induced mitochondrial adaptations in mouse skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 2014 Oct 1;307(7):R931-43. doi: 10.1152/ajpregu.00525.2013.

[3] Nielsen J, et al. Plasticity in mitochondrial cristae density allows metabolic capacity modulation in human skeletal muscle. J Physiol. 2017 May 1;595(9):2839-2847. doi: 10.1113/JP273040.

[4] Demongeot J, et al.  An open issue: the inner mitochondrial membrane (IMM) as a free boundary problem. Biochimie. 2007 Sep;89(9):1049-57. doi: 10.1016/j.biochi.2007.04.009.

[5] Picard M, et al. Acute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle. J Appl Physiol (1985). 2013 Nov;115(10):1562-71. doi: 10.1152/japplphysiol.00819.2013.

[6] Little JP, Safdar A, Bishop D, Tarnopolsky MA, Gibala MJ. An acute bout of high-intensity interval training increases the nuclear abundance of PGC-1α and activates mitochondrial biogenesis in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 2011 Jun;300(6):R1303-10. doi: 10.1152/ajpregu.00538.2010. Epub 2011 Mar 30. PMID: 21451146.

[7] MacInnis MJ, et al. Superior mitochondrial adaptations in human skeletal muscle after interval compared to continuous single-leg cycling matched for total work. J Physiol. 2017 May 1;595(9):2955-2968. doi: 10.1113/JP272570.

[8] Gibala MJ, et al. Short-term sprint interval versus traditional endurance training: similar initial adaptations in human skeletal muscle and exercise performance. J Physiol. 2006 Sep 15;575(Pt 3):901-11. doi: 10.1113/jphysiol.2006.112094.

[9] Henriksson J & Reitman JS. Time course of changes in human skeletal muscle succinate dehydrogenase and cytochrome oxidase activities and maximal oxygen uptake with physical activity and inactivity. Acta Physiol Scand. 1977 Jan;99(1):91-7. doi: 10.1111/j.1748-1716.1977.tb10356.x.

[10] Egan B, et al. Time course analysis reveals gene-specific transcript and protein kinetics of adaptation to short-term aerobic exercise training in human skeletal muscle. PLoS One. 2013 Sep 12;8(9):e74098. doi: 10.1371/journal.pone.0074098.

[11] Deng X, et al. Promotion of Mitochondrial Biogenesis via Activation of AMPK-PGC1ɑ Signaling Pathway by Ginger (Zingiber officinale Roscoe) Extract, and Its Major Active Component 6-Gingerol. J Food Sci. 2019 Aug;84(8):2101-2111. doi: 10.1111/1750-3841.14723.

[12] Mitrofanis J & Henderson LA. How and why does photobiomodulation change brain activity? Neural Regen Res. 2020 Dec;15(12):2243-2244. doi: 10.4103/1673-5374.284989.

[13] Nguyen LM, et al. Effect of near-infrared light exposure on mitochondrial signaling in C2C12 muscle cells. Mitochondrion. 2014 Jan;14(1):42-8. doi: 10.1016/j.mito.2013.11.001.

[14] Bevilacqua L, et al. Effects of short- and medium-term calorie restriction on muscle mitochondrial proton leak and reactive oxygen species production. Am J Physiol Endocrinol Metab. 2004 May;286(5):E852-61. doi: 10.1152/ajpendo.00367.2003.

[15] Civitarese AE, et al.; CALERIE Pennington Team. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 2007 Mar;4(3):e76. doi: 10.1371/journal.pmed.0040076.

[16] Kyriazis ID, et al. The impact of diet upon mitochondrial physiology (Review). Int J Mol Med. 2022 Nov;50(5):135. doi: 10.3892/ijmm.2022.5191. Epub 2022 Sep 21.

[17] Crane JD, et al. Massage therapy attenuates inflammatory signaling after exercise-induced muscle damage. Sci Transl Med. 2012 Feb 1;4(119):119ra13. doi: 10.1126/scitranslmed.3002882.

[18] Hafen PS, et al. Repeated exposure to heat stress induces mitochondrial adaptation in human skeletal muscle. J Appl Physiol (1985). 2018 Nov 1;125(5):1447-1455. doi: 10.1152/japplphysiol.00383.2018.

[19] Yao K, et al. Carvedilol promotes mitochondrial biogenesis by regulating the PGC-1/TFAM pathway in human umbilical vein endothelial cells (HUVECs). Biochem Biophys Res Commun. 2016 Feb 19;470(4):961-6. doi: 10.1016/j.bbrc.2016.01.089.

[20] Tao LC, et al. The Role of Mitochondrial Biogenesis Dysfunction in Diabetic Cardiomyopathy. Biomol Ther (Seoul). 2022 Sep 1;30(5):399-408. doi: 10.4062/biomolther.2021.192.

[21] Chodari L, et al. Targeting Mitochondrial Biogenesis with Polyphenol Compounds. Oxid Med Cell Longev. 2021 Jul 12;2021:4946711. doi: 10.1155/2021/4946711.

[22] Shin SY, et al. SIRT1 activation by methylene blue, a repurposed drug, leads to AMPK-mediated inhibition of steatosis and steatohepatitis. Eur J Pharmacol. 2014 Mar 15;727:115-24. doi: 10.1016/j.ejphar.2014.01.035. 

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