Health & Environmental Research Online (HERO)


Print Feedback Export to File
7164511 
Journal Article 
Inhibition of Mitochondrial Pyruvate Transport by Zaprinast Causes Massive Accumulation of Aspartate at the Expense of Glutamate in the Retina 
Du, J; Sadilek, M; Satrustegui, J; Sweet, I; Paquet-Durand, F; Hurley, JB; Cleghorn, WM; Contreras, L; Lindsay, Ken; Rountree, AM; Chertov, AO; Turner, SJ; Sahaboglu, A; Linton, J; , 
2013 
Yes 
Journal of Biological Chemistry
ISSN: 0021-9258
EISSN: 1083-351X 
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC 
BETHESDA 
288 
50 
36129-36140 
English 
24187136 
WOS:000329814700047 
Background: Pyruvate transport into mitochondria is a key step in energy metabolism. Zaprinast is a well known phosphodiesterase inhibitor. Results: Zaprinast has a strong influence on pyruvate transport into mitochondria. Conclusion: Inhibition of the mitochondrial pyruvate carrier by Zaprinast causes accumulation of aspartate at the expense of glutamate. Significance: Maintenance of normal amino acid levels in the retina relies on pyruvate transport into mitochondria.Transport of pyruvate into mitochondria by the mitochondrial pyruvate carrier is crucial for complete oxidation of glucose and for biosynthesis of amino acids and lipids. Zaprinast is a well known phosphodiesterase inhibitor and lead compound for sildenafil. We found Zaprinast alters the metabolomic profile of mitochondrial intermediates and amino acids in retina and brain. This metabolic effect of Zaprinast does not depend on inhibition of phosphodiesterase activity. By providing C-13-labeled glucose and glutamine as fuels, we found that the metabolic profile of the Zaprinast effect is nearly identical to that of inhibitors of the mitochondrial pyruvate carrier. Both stimulate oxidation of glutamate and massive accumulation of aspartate. Moreover, Zaprinast inhibits pyruvate-driven O-2 consumption in brain mitochondria and blocks mitochondrial pyruvate carrier in liver mitochondria. Inactivation of the aspartate glutamate carrier in retina does not attenuate the metabolic effect of Zaprinast. Our results show that Zaprinast is a potent inhibitor of mitochondrial pyruvate carrier activity, and this action causes aspartate to accumulate at the expense of glutamate. Our findings show that Zaprinast is a specific mitochondrial pyruvate carrier (MPC) inhibitor and may help to elucidate the roles of MPC in amino acid metabolism and hypoglycemia.