Master your cellular energy production for peak performance, vitality, and longevity, Start the 11-part series below.
Mitochondria are not fixed in number. The body can create new ones, increase its total mitochondrial capacity, and renew its cellular energy infrastructure in response to the right signals. This process is called mitochondrial biogenesis, and it is one of the most important mechanisms through which the body maintains and improves its health.
The difference between a live human and a dead one is that their mitochondria are dead; the dead body has all the organs, the systems, the cells but their mitochondria are no longer functioning.
More mitochondria means more capacity to produce energy. Which means walking more, running faster, recovering from exhaustion more quickly, and generally feeling full of life. The science of how this happens, and how to influence it, is both compelling and clinically significant.
Mitochondrial biogenesis is the process by which cells create new mitochondria. It involves a coordinated increase in mitochondrial mass, number, and function, driven by the activation of specific genes in both the cell’s nucleus and the mitochondria themselves.
Biogenesis does not produce mitochondria from scratch. New mitochondria grow from existing ones, enlarging and dividing through the process of fission. The cell increases production of the proteins and lipids required to build mitochondrial membranes and internal machinery, then divides the enlarged mitochondrion into two new ones. The result is an expanded mitochondrial network with greater capacity for ATP production, improved stress response, and enhanced metabolic flexibility.
At the heart of mitochondrial biogenesis is a protein called PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator 1-alpha). PGC-1alpha functions as the master regulator of mitochondrial production. When it is activated, it sets off a cascade of gene expression that directs the cell to build new mitochondrial components, increase the production of enzymes involved in energy metabolism, and enhance the cell’s overall oxidative capacity.
PGC-1alpha coordinates with a network of nuclear receptors and transcription factors to drive the broad program of mitochondrial expansion. Among the key downstream effects are increased expression of the proteins in the electron transport chain, expansion of mitochondrial membrane surface area, and improved efficiency of oxidative phosphorylation.
Understanding PGC-1alpha is central to understanding how biogenesis can be influenced, because the triggers for PGC-1alpha activation are things that can be deliberately sought or supported.
The signals that activate biogenesis share a common theme: they communicate that the cell’s current energy supply is insufficient to meet demand, or that the environment is placing new demands on the cell’s adaptive capacity. The body responds by building more mitochondria.
Exercise. Endurance exercise is the most potent natural stimulus for mitochondrial biogenesis. Physical activity depletes ATP, activates a cellular energy sensor called AMPK (AMP-activated protein kinase), and triggers PGC-1alpha activation. Studies have demonstrated that repeated bouts of endurance exercise significantly increase mitochondrial density in skeletal muscle. The effect is consistent across age groups, though the magnitude of the response changes with age.
Caloric restriction and fasting. Periods of reduced caloric intake activate energy-sensing pathways similar to those triggered by exercise, including AMPK activation, and can stimulate biogenesis through overlapping mechanisms.
Cold exposure. Exposure to cold temperatures can activate biogenesis in certain tissues, particularly brown adipose tissue, through mechanisms that involve thermogenic signaling.
Mitochondrial biogenesis is not a constant process. It responds to signals, and over time, the sensitivity to those signals decreases.
Research shows that mitochondrial capacity peaks around age 21. From that point forward, the body loses approximately 15 percent of its mitochondrial density every decade. This is called Aging. A significant contributor to this decline is reduced biogenesis activity: PGC-1alpha expression and activation become less responsive with age, and the body’s capacity to build new mitochondria in response to the same stimuli decreases.
This decline compounds other age-related changes. As damaged mitochondria accumulate and mitophagy becomes less efficient, the population of high-quality, functional mitochondria shrinks. Without robust biogenesis to replenish them, the cell’s energy capacity steadily declines.
As Dr. Sundeep Dugar has explained: “That is aging. That is when you start losing your muscle strength. Your metabolism slows down. No matter how hard you try, you gain weight. As you get older, you start losing memory.” These are not separate problems with separate causes. They are different expressions of the same underlying process: declining mitochondrial capacity across multiple organ systems.
The significance of mitochondrial biogenesis extends well beyond performance and aging. It has direct clinical relevance across a range of conditions in which mitochondrial dysfunction plays a central role:
Metabolic disorders. Insulin resistance and type 2 diabetes are closely associated with impaired mitochondrial biogenesis and reduced metabolic flexibility. Supporting biogenesis may help restore the cell’s capacity to manage glucose and fat effectively.
Cognitive decline. Given the brain’s extraordinary dependence on mitochondrial energy production, impaired biogenesis in neurons has implications for memory, processing speed, and long-term neurological health.
Neuromuscular diseases. In Becker muscular dystrophy and related conditions, impaired mitochondrial function contributes to progressive muscle deterioration. Clinical trials using (-)-epicatechin have demonstrated improvements in muscle strength and markers of mitochondrial regeneration in affected individuals.
Chronic kidney disease. Mitochondrial dysfunction in renal cells contributes to the progression of kidney disease. Clinical investigation into biogenesis-supporting compounds is ongoing at institutions including the Karolinska Institutet in Sweden.
Neurodegenerative decline. Each decade losing 10-15% of the mitochondria permanently plus poor mitophagy and increased ROS production among other factors means the mitochondria start to fail at fundamental maintenance, including the processing and clearing of amyloid precursor protein (APP), which plays an important role in neural growth, maturation and neural plasticity.
Mitochondria and Metabolic Health , Mitochondrial Health for Cognitive Performance
Connecting Obesity and Neurodegeneration – Dr. Robert Lustig
The body’s capacity for biogenesis can be supported through a combination of approaches:
The key insight from the science is that biogenesis is not passive. It is responsive. The body builds new mitochondria when it receives the right signals. The question is whether those signals are being consistently and effectively delivered.
Mitochondrial health is a rich, interconnected field. The pages in this knowledge hub explore each dimension in greater depth, from the molecular mechanics of biogenesis and mitophagy to the relationship between mitochondria and specific health conditions.
This content is for educational purposes only and is not medical advice. Consult a healthcare professional for guidance specific to your situation.
Studies, articles and talks behind this page.
McDonald, Craig M., Israel Ramirez-Sanchez, Björn Oskarsson, Nanette Joyce, et al. “(−)-Epicatechin Induces Mitochondrial Biogenesis and Markers of Muscle Regeneration in Adults with Becker Muscular Dystrophy.” Muscle & Nerve 63, no. 2 (2021): 239–49. https://doi.org/10.1002/mus.27108. Free full text
Jäger, Sibylle, Christoph Handschin, Julie St.-Pierre, and Bruce M. Spiegelman. “AMP-Activated Protein Kinase (AMPK) Action in Skeletal Muscle via Direct Phosphorylation of PGC-1α.” Proceedings of the National Academy of Sciences 104, no. 29 (2007): 12017–22. https://doi.org/10.1073/pnas.0705070104. Free full text
Dugar, Sundeep, Francisco Villarreal, Frank H. Hollinger, and Dinesh Mahajan. “11-β-Hydroxysterols as Possible Endogenous Stimulators of Mitochondrial Biogenesis as Inferred from Epicatechin Molecular Mimicry.” Pharmacological Research 151 (2020): 104540. https://doi.org/10.1016/j.phrs.2019.104540.
Dugar, Sundeep. “The Role of Mitochondria and Bioenergetics in the Skeletal and Cardiac Muscles of Becker Muscular Dystrophy: Overview.” BlueOakNx Blog.
Dugar, Sundeep. “Let’s Talk Mitochondria and the Discovery and Role of a New Steroid.” BlueOakNx Blog. Watch
Dugar, Sundeep. “Can One Molecule Mimic the Benefits of Exercise?” Bioregulators & Peptide Summit. DrTalks video.
Codino, Heidi, and Sundeep Dugar. “Is Estrogen a Mimic of Exercise to Stimulate Mitochondrial Biogenesis?” BlueOakNx Blog.
Civitarese, Anthony E., Stacy Carling, Leonie K. Heilbronn, Mathew H. Hulver, Barbara Ukropcova, Walter A. Deutsch, Steven R. Smith, and Eric Ravussin. “Calorie Restriction Increases Muscle Mitochondrial Biogenesis in Healthy Humans.” PLoS Medicine 4, no. 3 (2007): e76. https://doi.org/10.1371/journal.pmed.0040076. Free full text
Wu, Zhidan, Pere Puigserver, Ulf Andersson, Chenyu Zhang, Guillaume Adelmant, Vamsi Mootha, Amy Troy, et al. “Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1.” Cell 98, no. 1 (1999): 115–24. https://doi.org/10.1016/S0092-8674(00)80611-X.
Dugar, Sundeep. “The Powerhouse Within: Rebuilding Health Through Mitochondrial Regeneration.” Interview by Jaban Moore. MedMaps 2026. DrTalks video.
This content is for educational purposes only and is not medical advice. Consult a healthcare professional for guidance specific to your situation.
