Deletion of thioredoxin-interacting protein in mice impairs mitochondrial function but protects the myocardium from ischemia-reperfusion injury

Jun Yoshioka, William A. Chutkow, Samuel Lee, Jae Bum Kim, Jie Yan, Rong Tian, Merry L Lindsey, Edward P. Feener, Christine E. Seidman, Jonathan G. Seidman, Richard T. Lee

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

Classic therapeutics for ischemic heart disease are less effective in individuals with the metabolic syndrome. As the prevalence of the metabolic syndrome is increasing, better understanding of cardiac metabolism is needed to identify potential new targets for therapeutic intervention. Thioredoxin-interacting protein (Txnip) is a regulator of metabolism and an inhibitor of the antioxidant thioredoxins, but little is known about its roles in the myocardium. We examined hearts from Txnip-KO mice by polony multiplex analysis of gene expression and an independent proteomic approach; both methods indicated suppression of genes and proteins participating in mitochondrial metabolism. Consistently, Txnip-KO mitochondria were functionally and structurally altered, showing reduced oxygen consumption and ultrastructural derangements. Given the central role that mitochondria play during hypoxia, we hypothesized that Txnip deletion would enhance ischemia-reperfusion damage. Surprisingly, Txnip-KO hearts had greater recovery of cardiac function after an ischemia-reperfusion insult. Similarly, cardiomyocyte-specific Txnip deletion reduced infarct size after reversible coronary ligation. Coordinated with reduced mitochondrial function, deletion of Txnip enhanced anaerobic glycolysis. Whereas mitochondrial ATP synthesis was minimally decreased by Txnip deletion, cellular ATP content and lactate formation were higher in Txnip-KO hearts after ischemia-reperfusion injury. Pharmacologic inhibition of glycolytic metabolism completely abolished the protection afforded the heart by Txnip deficiency under hypoxic conditions. Thus, although Txnip deletion suppresses mitochondrial function, protection from myocardial ischemia is enhanced as a result of a coordinated shift to enhanced anaerobic metabolism, which provides an energy source outside of mitochondria.

Original languageEnglish (US)
Pages (from-to)267-279
Number of pages13
JournalJournal of Clinical Investigation
Volume122
Issue number1
DOIs
StatePublished - Jan 3 2012

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Thioredoxins
Reperfusion Injury
Myocardium
Proteins
Mitochondria
Myocardial Ischemia
Mouse Txnip protein
Ischemia
Adenosine Triphosphate
Anaerobiosis
Protein Deficiency
Recovery of Function
Glycolysis
Cardiac Myocytes
Oxygen Consumption
Proteomics
Reperfusion
Ligation
Lactic Acid
Antioxidants

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Deletion of thioredoxin-interacting protein in mice impairs mitochondrial function but protects the myocardium from ischemia-reperfusion injury. / Yoshioka, Jun; Chutkow, William A.; Lee, Samuel; Kim, Jae Bum; Yan, Jie; Tian, Rong; Lindsey, Merry L; Feener, Edward P.; Seidman, Christine E.; Seidman, Jonathan G.; Lee, Richard T.

In: Journal of Clinical Investigation, Vol. 122, No. 1, 03.01.2012, p. 267-279.

Research output: Contribution to journalArticle

Yoshioka, J, Chutkow, WA, Lee, S, Kim, JB, Yan, J, Tian, R, Lindsey, ML, Feener, EP, Seidman, CE, Seidman, JG & Lee, RT 2012, 'Deletion of thioredoxin-interacting protein in mice impairs mitochondrial function but protects the myocardium from ischemia-reperfusion injury', Journal of Clinical Investigation, vol. 122, no. 1, pp. 267-279. https://doi.org/10.1172/JCI44927
Yoshioka, Jun ; Chutkow, William A. ; Lee, Samuel ; Kim, Jae Bum ; Yan, Jie ; Tian, Rong ; Lindsey, Merry L ; Feener, Edward P. ; Seidman, Christine E. ; Seidman, Jonathan G. ; Lee, Richard T. / Deletion of thioredoxin-interacting protein in mice impairs mitochondrial function but protects the myocardium from ischemia-reperfusion injury. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 1. pp. 267-279.
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