Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury.
Elevated levels of branched-chain amino acids (BCAAs) have recently been implicated in the development of cardiovascular and metabolic diseases, but the molecular mechanisms are unknown. In a mouse model of impaired BCAA catabolism (knockout [KO]), we found that chronic accumulation of BCAAs suppressed glucose metabolism and sensitized the heart to ischemic injury. High levels of BCAAs selectively disrupted mitochondrial pyruvate utilization through inhibition of pyruvate dehydrogenase complex (PDH) activity. Furthermore, downregulation of the hexosamine biosynthetic pathway in KO hearts decreased protein O-linked N-acetylglucosamine (O-GlcNAc) modification and inactivated PDH, resulting in significant decreases in glucose oxidation. Although the metabolic remodeling in KO did not affect baseline cardiac energetics or function, it rendered the heart vulnerable to ischemia-reperfusion injury. Promoting BCAA catabolism or normalizing glucose utilization by overexpressing GLUT1 in the KO heart rescued the metabolic and functional outcome. These observations revealed a novel role of BCAA catabolism in regulating cardiac metabolism and stress response.
West China-Washington Mitochondria and Metabolism Center and Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PRC; Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Tao
T
Li
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Zhen
Z
Zhang
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Stephen C
SC
Kolwicz
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Lauren
L
Abell
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Nathan D
ND
Roe
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Maengjo
M
Kim
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Bo
B
Zhou
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Yang
Y
Cao
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Julia
J
Ritterhoff
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Haiwei
H
Gu
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Daniel
D
Raftery
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Haipeng
H
Sun
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA. Electronic address: rongtian@uw.edu.
Rong
R
Tian
D000117:Acetylglucosamine / Q000378:metabolism; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D005947:Glucose / Q000378:metabolism*; D006031:Glycosylation; D006334:Heart Function Tests; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology
D000597:Amino Acids, Branched-Chain; D011768:Pyruvate Dehydrogenase Complex; D019289:Pyruvic Acid; D005947:Glucose; D000117:Acetylglucosamine
N-glcNacation; branched-chain amino acids; cardiac metabolism; glucose; ischemia-reperfusion; mitochondria; pyruvate dehydrogenase