Branched-Chain Amino Acids and Mitochondrial Biogenesis: An Overview and Mechanistic Summary

Abstract

Branched-chain amino acids (BCAA) are essential in the diet and promote several vital cell responses which may have benefits for health and athletic performance, as well as disease prevention. While BCAA are well-known for their ability to stimulate muscle protein synthesis, their effects on cell energetics are also becoming well-documented, but these receive less attention. In this review, much of the current evidence demonstrating BCAA ability (as individual amino acids or as part of dietary mixtures) to alter regulators of cellular energetics with an emphasis on mitochondrial biogenesis and related signaling is highlighted. Several studies have shown, both in vitro and in vivo, that BCAA (either individual or as a mixture) may promote signaling associated with increased mitochondrial biogenesis including the upregulation of master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as numerous downstream targets and related function. However, sparse data in humans and the difficulty of controlling variables associated with feeding studies leave the physiological relevance of these findings unclear. Future well-controlled diet studies will be needed to assess if BCAA consumption is associated with increased mitochondrial biogenesis and improved metabolic outcomes in healthy and/or diseased human populations.

Keywords: isoleucine; leucine; mitochondrial biogenesis; skeletal muscle; valine.

Figure 1

Mechanistic overview of the potential link between BCAA and mitochondrial biogenesis. ① BCAA stimulate protein synthesis through multiple mechanisms which activates mammalian/mechanistic target of rapamycin complex 1 (mTORC1), ② a known activator of yin‐yang 1 (YY1) which works with peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α) to ③ promote mitochondrial biogenesis. ④ Increased protein synthesis associated with mTOR activation increases ATP consumption and AMP‐activated protein kinase (AMPK) activation. Along with activation of the ⑤ endothelial nitric oxide synthase (eNOS), ⑥ Sirtuin 1 (SIRT1), and ⑦ AMPK pathways, activated PGC‐1α works in conjunction with PPARs (peroxisome proliferator‐activated receptor alpha (PPARα) and peroxisome proliferator‐activated receptor beta (PPARβ)) to stimulate ⑧ mitochondrial biogenesis, ⑨ drive its own (PGC‐1α) expression, and ⑩ increase lipolytic and BCAA catabolic enzyme expression (including the mitochondrial catabolic enzymes associated with BCAA catabolism). ⑪ Leucine activation of mammalian/mechanistic target of rapamycin complex 2 (mTORC2) may also promote mitochondrial function. Other abbreviations: Bcat2, branched‐chain amino acid transaminase 2; Bckdh, branched‐chain alpha‐keto acid dehydrogenase; Cpt1, carnitine palmitoyl transferase 1; GATOR, GAP activity towards Rags; LAT1, complex, large neutral amino acid transporter 1; Nrf, nuclear respiratory factor; Tfam, mitochondrial transcription factor A; and SAR1B, secretion associated Ras related GTPase 1B. “?” indicates these observations are still unclear and warrant additional study.