Therapeutic Targets

Out with the Old: The Mitochondrial “Picture of Health” Begins with Destruction

“The most beautiful stories always start with wreckage.” – Jack London

Energy not only drives our daily activities—it ensures the health and longevity of our trillions of cells.  Conversion of food molecules into usable fuel occurs in tiny energy factories called mitochondria.  Historically dubbed the “energy powerhouses” and the “hub of energy metabolism” in textbooks, these organelles do more than simply recharge our bodies—they control cellular survival mechanisms that affect our health.1-3  Their promise and importance in medicine, upheld by the current scientific consensus, can be captured in simple words:  A cell with a flourishing network of mitochondria is generally a healthier one. 

Because they are short-lived, the mitochondria you have today are not the ones you had a month ago.  Such an ephemeral existence is the result of a dirty operation called energy metabolism, whose reactive byproducts—like sparks from a fire—slowly damage membranes and machinery.3,4  As the valiant engines fail, energy output dwindles.  More importantly, the defunct mitochondria become toxic when they accumulate, disrupting vital cellular functions.5

Old, insidious mitochondria are routinely destroyed through a process known as mitophagy.  The recycled parts are salvaged to create new mitochondria (a process called mitochondrial biogenesis).  This sustainable system hums when we’re young, but grows sluggish with time, weakening muscles and driving other hallmarks of aging.6,7  For instance, diminished mitophagy is linked to fatigue and decreased strength in preclinical models of aging.  

In lifestyle medicine, an evolving spotlight on mitophagy has deepened our definition of a mitochondrial “picture of health” and how to achieve it.   Popular modalities like caloric restriction, exercise and resveratrol supplementation support healthy aging, in part, through supporting or refurbishing mitochondrial networks.9,10  But until recently, safe and effective dietary agents that specifically target mitophagy have been sparsely studied.  

Figure 1. Mitochondrial renewal requires mitophagy (removal of dysfunctional structures) and mitochondrial biogenesis (the formation of new units). Urolithin A and resveratrol are polyphenols that support this coordinated process.

In a 2016 study published in Nature Medicine, a first-in-class natural phenolic compound called urolithin A (UA) stimulated mitophagy in preclinical models and improved muscle function and exercise capacity in two different rodent models.  UA also improved muscle strength and longevity in C. elegans, a preclinical paradigm of human aging, increased endurance and exercise capacity in both young and old animals.11  In agreement with these discoveries, 4 weeks of UA supplementation in healthy elderly subjects improved muscle mitochondrial gene expression and fatty acid oxidation efficacy, further supporting mitochondrial efficacy.12  UA supplementation resulted in improved mitochondrial function comparable to a 10-week aerobic exercise regimen, as measured by decreases in plasma acylcarnitine.

Urolithin A is a metabolite of ellagitannins and ellagic acid—major health-promoting constituents of pomegranates, nuts and berries.  These unique polyphenols undergo metabolism by intestinal bacteria to small, highly absorbable metabolites called urolithins, which mediate the widely acclaimed health benefits of pomegranates and ellagitannin-rich foods.13,14     

Owing to variations in gut microbiota, not everyone can generate UA after consuming these foods.15   Even with the right conversion “metabotype,” intestinal extraction of UA from ellagitannins is incomplete, unpredictable and impeded by aging, making oral UA—a universally absorbed molecule—appropriate for precise dosing and evidence-based use.16  Not surprisingly, pure oral UA outperforms pomegranate in its pharmacokinetic profile, as shown in a trial of healthy adults whose plasma UA levels were six times higher following a single dose of UA compared to an 8 oz serving of pomegranate juice, one of the richest sources of ellagitannins.17

Summary for Clinicians & Students

  • Conversion of food molecules to usable fuel (ATP) occurs in mitochondria.  These structures are delicate and short-lived, requiring continuous replacement. 
  • Cells renew mitochondria by clearing out old or superfluous structures in a process called mitophagy.  New structures are built with recycled parts in a process called mitochondrial biogenesis. 
  • When this renewal system loses efficiency, old mitochondria accumulate and become toxic, accelerating age-associated energetic and functional decline in skeletal muscle, brain and other tissues. 
  • Caloric restriction, resveratrol and metformin support mitochondrial biogenesis.  Until recently, safe and effective dietary supplements that specifically target mitophagy have been sparsely studied.  
  • Urolithin A (UA) is a natural compound that stimulates mitophagy in preclinical paradigms of aging and augments markers of mitochondrial performance and muscle function in humans.     

References

  1. Pizzorno J.  Integr Med (Encinitas). 2014 Apr; 13(2): 8–15.
  2. Um J-H, Yun J. BMB Rep. 2017 Jun;50(6):299-307. 
  3. Duchen MR. Diabetes 2004 Feb; 53(suppl 1): S96-S102.
  4. Roberts RG. PLoS Biol. 2017 Mar; 15(3): e2002338.
  5. Ashrafi G, Schwarz TL. Cell Death Differ. 2013 Jan;20(1):31-42.  
  6. Marzetti E, Calvani R, Cesari M, et al. Int J Biochem Cell Biol. 2013;45(10):2288-2301.
  7. Chen G, Kroemer G, Kepp O. Front Cell Dev Biol. 2020;8:200. 
  8. Sebastián D, Sorianello E, Segalés J, et al. EMBO J. 2016;35(15):1677-1693.
  9. Ruetenik A, Barrientos A.  Biochim Biophys Acta. 2015 Nov; 1847(11): 1434–1447.
  10. Menzies KJ. J Biol Chem. 2013 Mar 8; 288(10): 6968–6979.
  11. Ryu D, Mouchiroud L, Andreux PA, et al. Nature Medicine 22:8, 2016;879-88.
  12. Andreux PA, Blanco-Bose W, Ryu D, et al. Nature Metabolism 1:2019;595-603. 
  13. Espín JC, Larrosa M, García-Conesa MT, Tomás-Barberán F. Evid Based Complement Alternat Med. 2013;2013:270418.  
  14. Heim KC.  In:  Antioxidant Polymers: Synthesis, Properties, and Applications. Cirillo G, Iemma F, eds. Taylor and Francis, c. 2012
  15. García-Mantrana I et al. Nutrients. 2019 Oct; 11(10): 2483.
  16. Cortes-Martin A, Garcia-Villalba R, Gonzalez-Sarrias A, et al.  Food Funct. 2018, 9:4100-4106.
  17. Mitopure™ (Proprietary Urolithin A) Bioavailability in Healthy Adults (NOURISH). 2020.  https://clinicaltrials.gov/ct2/show/NCT04160312

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