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Toward a Mitochondrial “Picture of Health”: Simple Ways to Promote Cellular Energy Production

By Kelly C. Heim, Ph.D.*

Energy drives all of our daily physical and mental activities. Inside most of our 100 trillion cells, energy is made in mitochondria—tiny organelles that contain specialized enzymes and other protein machinery that takes the air we breathe (oxygen) and the food we eat (fats and carbohydrates) to generate cellular energy, known as adenosine triphosphate (ATP).

The medical importance of mitochondria goes beyond bioenergetics. Because of their roles in cellular signaling, neurotransmission, synaptic plasticity, insulin sensitivity, immune resilience, cell death and cell longevity, mitochondria have garnered considerable interest as targets for interventions in age-related conditions.1 Diminished mitochondrial number and fuction is a hallmark of aging and is regarded as an etiological component in metabolic, neurocognitive and cardiovascular conditions.2-4 In general, a cell with more mitochondria tends to be a healthier one.

In research settings, scientists measure mitochondrial function using biopsies and other procedures that cannot be deployed in routine clinical practice. With a limited and controversial assessment toolbox, objective definitions of mitochondrial health and dysfunction remain vague.5  Multisystem energy deficits can be presumed based on symptoms, with variable presentations including fatigue and muscular, metabolic or neurological symptoms. Even in rare cases of inherited mitochondrial disease, clinicians often struggle to identify the problem, relying heavily on basic evaluation and symptom recognition.6

The mitochondria have always held center stage in human nutrition, where macronutrients (carbohydrates and fats) elegantly cooperate with vitamin and mineral-supported enzymes to generate ATP. A 2022 publication on mineral requirements for mitochondrial function concluded that 11 out of the 12 major minerals localize to mitochondria and contribute to energy metabolism.7 These include zinc, which supports multiple subunits of the electron transport chain, magnesium, which stabilizes ATP, and selenium and manganese, which are cofactors for antioxidant enzymes that protect the mitochondrial membrane and DNA from free radicals produced during energy production. Additionally, B-vitamins (riboflavin, niacin and cobalamin) serve as vital cofactors for key steps in metabolism.8‡

The clinical translation of this textbook knowledge can fall short of expectations. Supplementation with vitamin and mineral cofactors doesn’t always move the bioenergetic needle unless there is an existing insufficiency. To understand the new paradigm of bioenergetics and the future of mitochondrial modalities, we need to take a step back and view these organelles not as single entities, but as dynamic, adaptable communities poised to adjust to new demands.

ENHANCING MITOCHONDRIAL QUALITY AND QUANTITY

Humans evolved on a dotted line of feasting and fasting over 6 million years, with recurrent food shortages shaping and fine-tuning our metabolism and physiology. Caloric restriction (CR), which includes fasting, intermittent fasting, alternate-day fasting and time-restricted eating, provides a controlled emulation of food scarcity that stimulates expansion of our cellular energy factories.9 CR activates AMP kinase (AMPK), an energy sensor that triggers the expression of genes that provide instructions to make new mitochondria (a process called mitochondrial biogenesis) and the removal of old, dysfunctional mitochondria (mitophagy).10, 11 Collectively termed mitochondrial quality control, both processes enhance the strength and size of mitochondrial networks, resulting in a higher overall cellular energy output.12 AMPK also activates sirtuins, which support healthspan and longevity.13

For most individuals, exercise is a more practical and sustainable option. Exercise enhances mitochondrial quality control without causing calorie deficit fatigue and immunosuppression associated with long-term CR protocols. Exercise works through a similar mechanism, activating AMPK, SIRT1 and downstream genes.14 In contrast to CR, exercise is anabolic to muscle and bone, and has cardiometabolic and neurological health benefits that go far beyond mitochondrial adaptations.

Moderate-intensity exercise is a powerful stimulus for mitochondrial biogenesis. Emerging evidence shows that high-intensity interval training (HIIT) may have comparable benefits.5, 15 Exercising twice per day (splitting one workout into two) was more effective than a single session in enhancing mitochondrial efficiency in a small study of healthy men.16 Adding a brisk daily morning walk (lasting at least 5 minutes) to an existing exercise program is an alternative way to boost daily exercise frequency. Regardless of intensity, a good workout should leave you feeling pleasantly tired, not exhausted. A good program should reduce resting heart rate while increasing cardiorespiratory fitness (VO2 max) after 6-8 weeks. It might take some time to find the best frequency and intensity to meet individual goals.

PHYTOCHEMICALS

Eating leafy greens, berries and other plants also supports mitochondrial number and quality. Throughout human evolution, eating plants foreshadowed periods of food scarcity, forcing metabolism to unlock more energy from less food. Leaves, roots and fruits contain polyphenols, terpenoids and other phytochemicals that can activate AMPK when consumed in sufficient amounts.17

Some natural compounds can be given orally as dietary supplements:

  • Resveratrol supports AMPK and mitochondrial function at daily doses of at least 150 mg/day.18‡
  • Pyrrolquinoline quinone (PQQ) is a B-vitamin-like antioxidant that supports mitochondrial biogenesis.19‡
  • Nicotinamide riboside and nicotinamide mononucleotide (NMN)provide NAD+, a cofactor that supports mitochondrial renewal. NAD+ is made from niacin, a B-vitamin, and its biosynthesis declines with age.20‡
  • Urolithin A (UA) is a metabolite of ellagitannins from pomegranates, nuts and berries. UA supports mitophagy and muscle function.21 In healthy elderly subjects, four weeks of UA supplementation improved biomarkers of muscle mitochondrial gene expression.22‡
  • Berberine supports glucose and lipid metabolism by supporting AMPK activation and mitochondrial biogenesis.23 Berberine is indicated when cardiometabolic support (glucose and/or lipids) is needed.‡

Refer to the Mitochondrial Health Protocol for specific product recommendations.

KEEP IT SIMPLE

Improving and maintaining mitochondrial health is about small, long-term lifestyle changes. Focus on the following:

  • Cover the basic biochemistry with a multivitamin or B-complex
  • Eat plants, with an emphasis on fresh leaves, cruciferous vegetables, berries and fruits.
  • Aim for a weekly goal of 150 minutes of total exercise per week. Include moderate-intensity physical activity, lasting at least 10 minutes at a time. A short walk or light exercise upon awakening, in the fasted state, may further potentiate the benefits of the overnight fast.
  • Consider recurring periods of calorie restriction. This could be as simple as eating dinner earlier and moving breakfast to a later time on certain days, creating a longer overnight fast. Aim for 16 hours of overnight fasting a couple of days per week.

RELATED LEARNING RESOURCES

Supporting AMPK Activation for Metabolic Health: A Practical Guide

Healthy Aging & the Importance of Building a Better Body Battery

Caloric Restriction: Basic Cellular Mechanisms

REFERENCES

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*Dr. Kelly Heim is an employee of Atrium Innovations, Inc.