Make More Mitochondria: Mitochondrial Biogenesis Part 1

Over the past few decades there has been considerable focus on the effect of exercise, diet, aging and disease on mitochondrial health.  Understanding the basic physiology of mitochondria and how they replicate in response to your lifestyle can have profound impacts on your overall health.

In this article I’ll share with you some insights gained from extensive research on the process of exercise-induced mitochondrial biogenesis – a term that refers to the synthesis of new mitochondria in muscle tissue.  Strap on your science helmet.

What are Mitochondria?

Mitochondria are cellular organelles that function as power plants within a cell.  In the same way that a local power plant produces electricity for an entire city, mitochondria are responsible for the production of energy derived from the breakdown of carbohydrates and fatty acids.  Mitochondria oxidize or “burn” carbohydrates, amino acids and fatty acids for energy, yielding ATP.  ATP is the cellular form of energy utilized by cellular processes all throughout the body, providing the energy to pump your heart, power neurons in your brain, contract muscles in your limbs, exchange gases in your lungs, extract nutrients from food and regulate body temperature, to name just a few.


Simply stated, mitochondria produce ATP, and ATP is absolutely essential for survival.  Without a sufficient generation of ATP, life would cease to exist.

Where are Mitochondria Found?

Mitochondria are located in every cell type and tissue in the human body, from your brain to your thyroid gland to your Achilles tendon.  In short – trillions of mitochondria are distributed all throughout your body with the sole purpose of generating ATP.  Red blood cells are the only cell type that do not contain mitochondria.


In this electron micrograph, many adjacent mitochondria are visible within the muscle cell.  It’s no coincidence that they are located close to one another – they do that in order to share glucose, amino acids and fatty acids in order to distribute the production of ATP across a coordinately linked network.

Scientists believe that mitochondria were once free living organisms that developed a symbiotic relationship with mammalian cells over millions of years of evolution.  The reason for this is simple – mitochondria contain their own DNA.  Mitochondria are the only subcellular organelle that contain DNA outside of the nucleus.  They contain a simpler, circular copy of DNA that is transcribed with nuclear DNA in a coordinated symphony when it comes time to synthesize more mitochondria.

Muscles contain the highest mitochondrial content of any tissue in your body, in order to provide massive amounts of ATP for movement and exercise.

Muscle is generally divided into three types – white muscle, red muscle and mixed muscle.  The terms “red” and “white” are derived from the way these muscles appear during surgery or autopsies, but largely refer to the mitochondrial content of the muscle itself.


Red muscles contain a large quantity of mitochondria, white muscles contain fewer mitochondria and mixed muscles contain both red and white muscle fiber types.  Whereas a single cell contains one nucleus, muscle cells often contain hundreds or even thousands of mitochondria in order to support the generation of large quantities of ATP during exercise.

What is Mitochondrial Biogenesis?

Mitochondrial biogenesis is a process that was first described over 40 years ago by a pioneer in the field of exercise physiology named John Holloszy, a professor at Washington University in St. Louis, MO.  Think of him as the godfather of exercise physiology.  In his seminal paper on the effects of exercise on mitochondrial structure and function, he found that endurance training induced large increases in muscle mitochondrial content and increased the ability of muscle to uptake glucose during and after exercise (1).

For more information on why glucose is your best friend during and after exercise, read How to Fuel Muscles During Exercise and What Happens to Muscles After Exercise?.

The term “mitochondrial biogenesis” simply refers to the process of replicating mitochondria within a cell, in order to increase ATP production in response to an increased demand for energy.

The result of mitochondrial biogenesis is an expansion of the network of mitochondria within a cell, and an increase in the maximal amount of ATP that can be generated during intense exercise.  In short – more mitochondria mean more ATP production at peak exercise conditions (2).

Muscle Mitochondria: Use Them or Lose Them!

Chronic disuse of muscle, sedentary behavior and aging each independently result in a decline in mitochondrial content and function, leading to the production of free radicals and cell death.  The muscle tissue of people with type 2 diabetes has also been extensively studied, revealing gross defects in mitochondrial number and function.  Although the cause-and-effect still remains unknown, muscle tissue from people with type 2 diabetes often is associated with reduced aerobic capacity, insulin resistance and deficient mitochondrial biogenesis (3,4).  In addition, studies have also shown that defective mitochondrial biogenesis in the heart can predispose individuals to cardiovascular complications, heart disease and the metabolic syndrome (5).


Luckily, reversing the effects of aging, diabetes and cardiovascular disease via increased mitochondrial biogenesis is as simple as exercising more.  Studies have shown that in aged individuals those with existing metabolic disease, the resumption of an active lifestyle can significantly improve preexisting cellular damage and promote gains in muscle mass (2).  Regular endurance exercise by itself (independent of changes in diet) can normalize age-related mitochondrial dysfunction simply by activating mitochondrial biogenesis (6).

Mitochondrial Dysfunction is a Hallmark of Insulin Resistance

Insulin resistance starts in the muscle and liver tissues as a result of excess fatty acid accumulation.  When muscle accumulates excess fatty acids over time, the muscle loses it’s ability to respond to insulin effectively.  Extensive scientific studies have shown that muscle tissue from subjects with type 2 diabetes is deficient in many crucial aspects of mitochondrial biology, including the following:

  • Reduced quantity of mitochondria (7,8)
  • Reduced ability to burn fatty acids and glucose for energy (4,9,10)
  • Impaired mitochondrial electron transport chain protein function (11)
  • Improper distribution of mitochondria within the muscle tissue (3)
  • Impaired mitochondrial gene expression (12)
Insulin resistance and diabetes are metabolic disasters for muscle tissue unless specific steps are taken to counteract mitochondrial dysfunction.

Since muscle tissue occupies more than 40% of the human body by mass, a reduced ability of muscle mitochondria to burn fatty acids and glucose for energy is partly responsible for feelings of low energy and sluggishness that many people with diabetes feel.  More importantly, defective muscle mitochondrial function often induces a mild inflammatory state within the muscle tissue that results in the production of blood borne cytokines that signal a state of stress to circulating immune cells.

Specific measures must be taken in order to counteract mitochondrial dysfunction due to insulin resistance, and in next week’s article we will explore how exercise can induce mitochondrial biogenesis extremely effectively.  Since mitochondria are responsive to the demand for energy created by exercise and the type of fuel available from the diet, a 2-pronged approach to eliminating insulin resistance is often the most effective way to restore muscle mitochondrial function and restore blood glucose values to normal.


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1.            Holloszy, J. O. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J. Biol. Chem. 242, 2278–2282 (1967).

2.            Hood, D. A. Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle. Appl. Physiol. Nutr. Metab. Physiol. Appliquée Nutr. Métabolisme 34, 465–472 (2009).

3.            Ritov, V. B. et al. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 54, 8–14 (2005).

4.            Sreekumar, R. & Nair, K. S. Skeletal muscle mitochondrial dysfunction & diabetes. Indian J. Med. Res. 125, 399–410 (2007).

5.            Nisoli, E., Clementi, E., Carruba, M. O. & Moncada, S. Defective Mitochondrial Biogenesis A Hallmark of the High Cardiovascular Risk in the Metabolic Syndrome? Circ. Res. 100, 795–806 (2007).

6.            Lanza, I. R. et al. Endurance exercise as a countermeasure for aging. Diabetes 57, 2933–2942 (2008).

7.            Martins, A. R. et al. Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function. Lipids Health Dis. 11, 30 (2012).

8.            Silveira, L. R. et al. Updating the effects of fatty acids on skeletal muscle. J. Cell. Physiol. 217, 1–12 (2008).

9.            Kelley, D. E., He, J., Menshikova, E. V. & Ritov, V. B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950 (2002).

10.          Kelley, D. E. Skeletal muscle fat oxidation: timing and flexibility are everything. J. Clin. Invest. 115, 1699–1702 (2005).

11.          Ritov, V. B. et al. Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity. Am. J. Physiol. Endocrinol. Metab. 298, E49–58 (2010).

12.          Sreekumar, R., Halvatsiotis, P., Schimke, J. C. & Nair, K. S. Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment. Diabetes 51, 1913–1920 (2002).

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About The Author

Cyrus Khambatta

Diagnosed with type 1 diabetes at the age of 22, I have spent over a decade learning the fundamentals of nutrition at the doctorate level. My goal is to share my knowledge of practical nutrition and fitness with people with prediabetes, type 1 and type 2 diabetes. Diabetes is an OPPORTUNITY to attain excellent health. Reversing the effects of insulin resistance can be a fun and enjoyable process if the right system is in place. That's why I've spent over 10 years developing a rock solid system that can minimize blood glucose variability and insulin resistance.

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