What are Mitochondria, Mitochondrial Biogenesis and How to Stimulate It

Mitochondria are often referred to as the energy powerhouse of the cells and, by extension, the body. It is one of several organelles contained in the cellular cytoplasm, crucial for the energy demands of the cells. Eukaryotes carry two types of DNA: the mitochondrial DNA (mtDNA) and Nuclear DNA. The two genomes work in harmony to manufacture the proteins that are needed for mitochondrial biogenesis.

Out of the 1,000-1,500 mitochondrial proteins needed for mitochondrial biogenesis, only 13 are encoded by the mtDNA, while the rest are encoded by nuclear DNA,synthesized in the cytosol and imported into mitochondria through specialized protein import mechanisms.

Through oxidative phosphorylation, mitochondria produce adenosine triphosphate (ATP), the primary energy currency of the cell. Since many cellular functions depend on adequate ATP supply, impaired mitochondrial health can disrupt mitochondrial biogenesis and contribute to pathological processes in the body.

In this article, we will discover what the mitochondrial biogenesis pathway is, how changes in it can impact your health, and common lifestyle strategies to keep it healthy.

What Is Mitochondrial Biogenesis and Why Is It Important?

This 2020 study titled: Mitochondrial Biogenesis: An Update, by Lucia-Doina Popov, defines mitochondrial biogenesis as: “a self-renewal route by which new mitochondria are generated from existing ones, launched by cells in response to energy demands triggered by developmental signals or environmental stressors.”

Simply put, mitochondrial biogenesis is the process through which cells generate new mitochondria from preexisting ones, often accompanied by an increase in mitochondrial mass. It’s a complex and highly regulated process, coordinated by mitochondrial and nuclear factors. This balance is maintained through mitochondrial dynamics– a system of fusion and fission events that preserve the organelle’s shape, structure, and function.

Although mitochondria contain their own DNA and can synthesize a small number of essential proteins, mitochondrial biogenesis depends primarily on the coordination of both mtDNA and the nuclear genome.

Mitochondrial biogenesis is a vital biological process that supports the constant energy demands of cells, ensuring normal physiological functions proceed without interruption. Beyond cellular respiration, mitochondria play key roles in energy metabolism, ion homeostasis, lipid regulation, and the initiation of apoptosis. When mitochondrial biogenesis is impaired, the ability to generate new mitochondria to sustain these processes is compromised, which can negatively affect overall health and contribute to conditions such as diabetes, cardiovascular disease, and age-related decline.

How Mitochondria Support Energy Production and Cellular Health

Without the mitochondria, eukaryotic cells would have to depend on glycolysis (and anaerobic pathway), a process that yields just two molecules of ATP per molecule of glucose. In contrast, oxidative phosphorylation yields an energy production in excess of 30 molecules of ATP for each molecule of glucose.

The oxidative phosphorylation system consists of five mitochondrial complexes and serves as the primary source of cellular energy by converting adenosine diphosphate (ADP) into adenosine triphosphate (ATP). The electron transport chain (ETC) is composed of the first four complexes, where electrons from reduced cofactors-NADH and FADH2, generated during the metabolism of glucose, fatty acids, and to a lesser extent, amino acids are transferred through these complexes.

As electrons flow, protons are pumped across the inner mitochondrial membrane, creating an electrochemical proton gradient. The fifth complex, ATP synthase, utilizes the proton-motive force to drive phosphorylation of ADP to ATP, completing the process of oxidative phosphorylation. The efficiency of the mitochondria in this process is essential for maintaining cellular health.

The Role of PGC-1α, AMPK, and SIRT1 in Mitochondrial Activation

The AMP-activated protein kinase (AMPK) helps trigger mitochondrial biogenesis pathways but is not the sole contributor. It acts as the fuel gauge of the cells, sensing when levels are low before activating the catabolic pathway that will eventually lead to the biogenesis of the mitochondria. This happens during cellular energy stress when energy levels shift, leading to an increase in the AMP/ATP ratio, which in turn activates the AMPK.

The activation of the AMPK enzyme enhances energy-generating processes such as fatty acid oxidation and glucose uptake to restore cellular energy homeostasis. In the longer term, AMPK also promotes mitochondrial biogenesis, leading to an increased number and efficiency of mitochondria, which strengthens the cell’s ability to produce ATP and mount a more effective cellular stress response. To achieve this, the AMPK enzyme works in concert with PGC-1alpha and SIRT1.

AMPK phosphorylates PGC-1alpha, increasing its activity. Additionally, it increases cellular NAD+ levels, which fosters SIRT1 activities. SIRT1, in turn, deacetylates PGC-1 alpha, which increases the efficiency of the enzyme to drive the transcription of mitochondrial genes. Active PGC-1alpha co-activates NRF1, GABP/NRF2, and ERR, which increases the expression of genes encoding mitochondrial respiratory chain proteins, mitochondrial import machinery, mitochondrial transcription factors, and enzymes for substrate oxidation.

How Exercise Stimulates Mitochondrial Biogenesis

According to a 2022 meta-analysis and systematic review, exercise training improves mitochondrial oxidative capacity in patients with cardiovascular diseases, with supportive evidence for positive changes in morphology and biogenesis.

The review screened 821 records across 20 studies involving patients with conditions such as heart failure, peripheral artery disease, stroke, coronary artery disease, and hypertension. The review reports exercise-related improvements in mitochondrial function in cardiovascular disease (CVD). Specifically, it notes that consistent exercise induces metabolic stress that, over time, drives skeletal muscle adaptations to better meet increased energy demands.

However, with regular training over several weeks, the body undergoes remarkable adaptations, one of which is an increase in the number of mitochondria produced and an improvement in aerobic energy production. Exercise can stimulate mitochondrial biogenesis in this sequence:

• Muscle contraction dramatically increases ATP demand, raising AMP/ADP levels and lowering energy charge. This signals the need for enhanced energy production.
• Exercise-induced increases in calcium, nitric oxide, reactive oxygen species, and AMP/ADP act as cues of stress. This activates signaling kinases such as AMPK.
• The AMPK signalling pathway facilitates the uptake of fatty acids and glucose into skeletal muscle.
• These acute responses provide immediate ATP supply. Repeated exercise bouts drive adaptive changes, including the activation of PCG-1alpha. Over time, this leads to increased mitochondrial content and improved function, preparing the muscle for future metabolic demands.

In a nutshell, exercise is a biogenesis stimulator. Exercise-induced biogenesis is especially important in the elderly because chronic exercise activates both AMPK and PGC-1α, which contribute to mitochondrial mass, energy homeostasis, thermoregulation, and glucose metabolism. These are critical processes that tend to decline with age.

Nutritional Factors and Supplements That Support Mitochondrial Growth

Several nutrients and supplements help mitochondria grow and function by boosting energy metabolism and protecting against stress. B-vitamins drive core metabolic pathways, while vitamin C, vitamin E, selenium, and lipoic acid act as antioxidants and cofactors that protect enzymes. Coenzyme Q10, carnitine, taurine, creatine, , and nitrates may support mitochondrial efficiency. However, more research is needed. Together, they have the potential to enhance energy output and strengthen cellular resilience.

The Impact of Caloric Restriction and Fasting on Mitochondria

ATP is produced from oxidative phosphorylation, a process that involves the production of reactive oxygen species (ROS) such as superoxide, hydrogen peroxide (and under some conditions, hydroxyl radicals) . The health of the mitochondria is therefore dependent on the balance between these reactive oxygen species and the antioxidant properties of the cell.

A disequilibrium occurs when higher levels of reactive oxygen species are produced against the antioxidant defenses of the cells, ultimately leading to oxidative stress and mitochondrial damage. Although mitochondria generate ROS, they also contain dedicated antioxidant systems (MnSOD/SOD2, GPx) so vulnerability stems from ROS generation. . To maintain cellular homeostasis, damaged mitochondria can be selectively removed through a process known as mitophagy, which helps prevent further oxidative injury and cell death.

Additionally, caloric restriction, whether through reduced calorie intake, dietary composition adjustments, or timing strategies such as intermittent fasting, can stimulate mitophagy and its associated biomarkers. Mitophagy plays a central role that maintains mitochondrial homeostasis, serving as a critical quality control by removing damaged mitochondria and balancing mitochondrial degradation with biogenesis. If you think intermittent fasting may be helpful for you, please do ask your medical doctor as it is not recommended for some health conditions.

Hormonal and Environmental Influences on Mitochondrial Biogenesis

While it is well established that nuclear genomes contain epigenetic marks such as DNA methylation and histone modifications, which can alter the expression of specific genes, mtDNA also carries epigenetic marks, mainly DNA methylation and RNA modification. However, the precise roles of these epigenetic modifications within mtDNA remain unclear. Hence, research has mainly focused on how modifications of the nuclear epigenome by different factors can influence mitochondrial biogenesis. Such factors include the environment and hormones.

Environmental factors such as endocrine disruptors, including bisphenols and phthalates commonly found in food packaging, can disrupt mitochondrial function and signaling, partially by affecting nuclear and mitochondrial DNA methylation. However, direct inhibition of mitochondrial biogenesis is primarily shown in experimental models and therefore we need some additional human studies. This disruption also extends to mtDNA methylation, but the greater consequence lies in how an altered nuclear epigenome can impair the coordination between the nuclear and mitochondrial genomes, which is essential for mitochondrial biogenesis.

For instance, DNA methylation, histone modifications, and non-coding RNAs regulate the expression of mitochondrial-related nuclear genes. A typical example is the PGC-1alpha, a master regulator of mitochondrial biogenesis, which is tightly controlled by epigenetic marks

How Aging Affects Mitochondrial Function and Regeneration

Aging and biogenesis function like opposing regulators of cellular homeostasis- aging diminishes mitochondrial bioenergetics, while biogenesis maintains resilience through renewal.

Aging is a biological process that occurs as a result of progressive changes in the function and structure of the cell. Changes in the mitochondrial dynamics at the subcellular level partly drive these changes. According to an aging theory, these changes occur because mtDNA is more prone to mutation due to proximity to ROS and relatively limited repair capacity compared to nuclear DNA. Mutations in the mtDNA can alter the oxidative phosphorylation pathway and may lead to mitochondrial dysfunction and accelerated ROS production.

Furthermore, ROS are byproducts of electron transport that can contribute to oxidative damage when not neutralized by antioxidants. Moreover, PCG-1a, the master regulator of mitochondrial biogenesis, is age-dependent and declines in activity over time. This reduction compromises mitochondrial dysfunction during aging.

Practical Lifestyle Strategies to Enhance Mitochondrial Health

We’ve already highlighted how exercise enhances mitochondrial health; however, more lifestyle strategies can enhance this organelle’s functionality, including:

• Adequate sleep;
• Stress management;
• Reduced exposure to pollutants;
• Relaxation techniques;
• Moderate amount of sunlight;
• Cold shower;
• Heat exposure;
• Supplements with mitochondrial boosting nutrients;

While these strategies cannot prevent the mitochondria from eventually aging and reducing their function, they are practical steps that can slow down this process and enhance the overall health of the cells and body.

Medical and Experimental Therapies Targeting Mitochondrial Biogenesis

Since mitochondrial biogenesis can be stimulated by various factors already discussed in this article, scientists believe that it can be pharmacologically manipulated as well. Diseases in which mitochondrial dysfunction plays a role include diabetes, neurodegenerative diseases (Alzheimer’s, Parkinson’s), mitochondrial ataxias, , retinitis pigmentosa, andLeigh’s syndrome. Generally, a mutation in the mtDNA is common in these disease states. They alter oxidative phosphorylation, which sets off a cascade of reactions that leads to the depletion of ATP.

According to the study on Mitochondrial Biogenesis as a Therapeutic Target for Neurodevelopmental Disorders and Neurodegenerative Diseases, exercise, targeted medicine and early interventions all hold therapeutic potential by enhancing mitochondrial biogenesis. have therapeutic potential for mitochondrial biogenesis.

However, pharmacological approaches aim to harness the signaling pathways governing mitochondrial biogenesis, primarily coordinated by the transcriptional coactivator peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1-alpha (PGC-1alpha). PGC-1alpha works in synchrony with transcription factors, including PPARs and Nuclear respiratory factors (NRFs), to regulate the expression of nuclear genes essential for mitochondrial function.

Building on this knowledge, several drugs targeting these pathways have shown promising results in animal models, and some are currently being evaluated in clinical trials. They include:

• Bezafibrate;
• REN001;
• Omaveloxolone;
• Epicatechin;
• Pioglitazone;
• Idebenone;
• Vatiquinone;
• Rapamycin;

None of these drugs are approved specifically for the therapeutic application of stimulating mitochondrial biogenesis. Their effects on these pathways are accidental, occurring alongside their established or investigational use.

Future Directions in Research on Mitochondrial Optimization

Genetic mitochondrial diseases highlight the urgent need for innovative strategies to enhance mitochondrial health and function. While existing treatments are mostly supportive, new technologies are creating opportunities for more targeted interventions. Some of these approaches include nanomedicine, gene editing technologies, and gene therapy.

Depending on what’s best for your system, options from exercise and fasting to targeted nutrients and stress reduction, support that the science is clear—your daily choices can either strengthen or weaken the mitochondria that fuel your body. By supporting biogenesis and protecting mitochondrial function, you’re not only boosting energy today but also laying the groundwork for long-term cellular resilience and healthy aging.

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Frequently Asked Questions

What exercises are good for mitochondrial biogenesis?

Generally, endurance exercises like running, cycling, and swimming- especially at moderate to high intensity- are best for stimulating mitochondrial biogenesis.

Does intermittent fasting increase mitochondria?

Yes. Research shows that intermittent fasting can trigger cellular stress responses and mitophagy. At the same time, more research is needed for evidence that it directly increases mitochondrial biogenesis.

How do stress and sleep quality affect mitochondrial biogenesis?

Chronic stress and poor sleep impair mitochondrial function and redox balance; suggesting an impairment to biogenesis by disrupting hormonal balance and increasing oxidative stress, while good sleep and stress management support healthy mitochondrial growth and function.

What foods are bad for mitochondria?

Foods high in processed sugars, trans fats, refined carbs, and excessive alcohol are harmful to mitochondria because they promote oxidative stress, inflammation, and impaired energy production.

Can mitochondrial biogenesis help with age-related decline in energy levels?

Yes. Mitochondrial biogenesis can counteract age-related energy decline by increasing the number and efficiency of mitochondria, which helps cells produce more ATP and maintain better overall energy metabolism as we age.

References

Mitochondrial biogenesis: An update

ROS Stress Response

Exercise and the Regulation of Mitochondrial Turnover

AMPK and the Adaptation to Exercise

Exercise activates AMPK signaling: Impact on glucose uptake in the skeletal muscle in aging

Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence

The effect of fasting or calorie restriction on mitophagy induction: a literature review

Impact of Dietary Restriction Regimens on Mitochondria, Heart, and Endothelial Function: A Brief Overview

Mitochondrial Epigenetics and Environmental Health: Making a Case for Endocrine Disrupting Chemicals

Epigenetic Control of Mitochondrial Function in the Vasculature

Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1

How Epigenetic Modifications Drive the Expression and Mediate the Action of PGC-1α in the Regulation of Metabolism

The role of estrogen in mitochondrial disease 

Hormonal regulation of mitochondrial energy production

Cortisol Regulates Cerebral Mitochondrial Oxidative Phosphorylation and Morphology of the Brain in a Region-Specific Manner in the Ovine Fetus

Elevated mitochondrial biogenesis in skeletal muscle is associated with testosterone-induced body weight loss in male mice

Mitochondrial Aging and Age-Related Dysfunction of Mitochondria

Moderate Modulation of Cardiac PGC-1α Expression Partially Affects Age-Associated Transcriptional Remodeling of the Heart

The Importance of Mitochondria & What Nutrients Support Their Health

Mitochondria: 10 Ways to Boost the Powerhouse of Your Cells

Mitochondrial biogenesis: pharmacological approaches

Therapies for Mitochondrial Disease: Past, Present, and Future

Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan; 2nd report QOL survey

Advancements in mitochondrial-targeted nanotherapeutics: overcoming biological obstacles and optimizing drug delivery