Deletion of thioredoxin-interacting protein in mice impairs mitochondrial function but protects the myocardium from ischemia-reperfusion injury
Jun Yoshioka, … , Jonathan G. Seidman, Richard T. Lee
Jun Yoshioka, … , Jonathan G. Seidman, Richard T. Lee
Published January 3, 2012; First published December 27, 2011
Citation Information: J Clin Invest. 2012;122(1):267-279. https://doi.org/10.1172/JCI44927.
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Research Article

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

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.

Authors

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

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Figure 1

Deletion of Txnip in the myocardium results in mitochondrial dysfunction with decreased expression of transcripts encoding mitochondrial metabolism.

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Deletion of Txnip in the myocardium results in mitochondrial dysfunction...
(A and B) PMAGE demonstrated transcriptional changes in mitochondrial metabolism–related pathways in Txnip-KO hearts. Gene ontology analysis was performed using the software PANTHER that classified downregulated genes by their molecular functions (A) and biological processes (B) based on published evidence. Biological process (B) covers the biological systems to which a protein contributes. Each group refers to a group of proteins with common function or process. (C and D) Respiration control ratio was obtained from permeabilized cardiac fibers incubated with indicated substrates in 11 WT and 7 Txnip-KO mice. (E–H) Representative tracing of oxygen consumption in isolated mitochondria (E and G). Mitochondria (200 μg) were incubated with 5 mM glutamate and 2 mM malate (E and F; n = 14 [WT] 13 [Txnip-KO]) or with 10 mM pyruvate and 2 mM malate (G and H; n = 4 each). State 2 and 3 respirations were measured by a Clark-type electrode in the presence of respiratory substrates before and after the addition of 1 mM ADP. State 4 respiration was measured on depletion of ADP. Values are mean ± SEM. *P < 0.05 versus WT.