Abstract
BackgroundMany methods have been used to assess mitochondrial function. Technetium-99m sestamibi (99mTc-MIBI), a lipophilic cation, is rapidly incorporated into myocardial cells by diffusion and mainly localizes to the mitochondria. The purpose of this study was to investigate whether measurement of 99mTc-MIBI signals in animal models could be used as a tool to quantify mitochondrial membrane potential at the organ level.Methods and ResultsWe analyzed 99mTc-MIBI signals in Sprague-Dawley (SD) rat hearts perfused with carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler known to reduce the mitochondrial membrane potential. 99mTc-MIBI signals could be used to detect changes in the mitochondrial membrane potential with sensitivity comparable to that obtained by two-photon laser microscopy with the cationic probe tetramethylrhodamine ethyl ester (TMRE). We also measured 99mTc-MIBI signals in the hearts of SD rats administered CCCP (4 mg/kg intraperitoneally) or vehicle. 99mTc-MIBI signals decreased in rat hearts administered CCCP, and the ATP content, as measured by 31P magnetic resonance spectroscopy, decreased simultaneously. Next, we administered 99mTc-MIBI to Dahl salt-sensitive rats fed a high-salt diet, which leads to hypertension and heart failure. The 99mTc-MIBI signal per heart tissue weight was inversely correlated with heart weight, cardiac function, and the expression of atrial natriuretic factor, a marker of heart failure, and positively correlated with the accumulation of labeled fatty acid analog. The 99mTc-MIBI signal per liver tissue weight was lower than that per heart tissue weight.ConclusionMeasurement of 99mTc-MIBI signals can be an effective tool for semiquantitative investigation of cardiac mitochondrial membrane potential in the SD rat model by using a chemical to decrease the mitochondrial membrane potential. The 99mTc-MIBI signal per heart tissue weight was inversely correlated with the severity of heart failure in the Dahl rat model.
Highlights
Technetium-99m sestamibi (99mTc-MIBI) is a lipophilic cation [1]
We analyzed 99mTc-MIBI signals in Sprague-Dawley (SD) rat hearts perfused with carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler known to reduce the mitochondrial membrane potential. 99mTc-MIBI signals could be used to detect changes in the mitochondrial membrane potential with sensitivity comparable to that obtained by two-photon laser microscopy with the cationic probe tetramethylrhodamine ethyl ester (TMRE)
We measured 99mTc-MIBI signals in the hearts of SD rats administered CCCP (4 mg/kg intraperitoneally) or vehicle. 99mTc-MIBI signals decreased in rat hearts administered CCCP, and the ATP content, as measured by 31P magnetic resonance spectroscopy, decreased simultaneously
Summary
Technetium-99m sestamibi (99mTc-MIBI) is a lipophilic cation [1]. Because cells have a negative transmembrane potential and a highly negative mitochondrial membrane potential, 99mTc-MIBI accumulates in the mitochondria in living cells [2] [3]. The 99mTc-MIBI content correlates with the expression of the mitochondrial inner matrix enzyme malate dehydrogenase and with mitochondrial substrates in isolated perfused hearts [5]. More than 90% of 99mTc-MIBI is localized to the mitochondrial fraction and is in proportion with the activity of succinate dehydrogenase, a mitochondrial marker, in hearts excised from animals 10 min after intravenous bolus administration [6]. Technetium-99m sestamibi (99mTc-MIBI), a lipophilic cation, is rapidly incorporated into myocardial cells by diffusion and mainly localizes to the mitochondria. The purpose of this study was to investigate whether measurement of 99mTc-MIBI signals in animal models could be used as a tool to quantify mitochondrial membrane potential at the organ level
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