The mitochondrial adenosine 5'-triphosphatase in slow and fast heart rate hearts

Abstract

A survey of 12 species has revealed that reversible ischemia-induced protonic inhibition of the cardiac muscle mitochondrial adenosine 5'-triphosphatase (ATPase) described by this author earlier (Rouslin, W. J. Biol. Chem. 258: 9657-9661, 1983) occurs only in animals with heart rates lower than approximately 200 beats/min. It was thus fully demonstrable in rabbit, dog, sheep, human, pig, and beef heart mitochondria. In contrast, the in situ ATPase inhibition was completely absent in six smaller species capable of heart rates of approximately 300 or more beats/min. These were chicken, pigeon, guinea pig, rat, hamster, and mouse. Analyses of the cardiac muscle mitochondria of 9 of the 12 species studied showed them to contain normal levels of mitochondrial ATPase inhibitor; the three smallest species, rat, hamster, and mouse contained only very low levels of inhibitor. Thus, although chicken, pigeon, and guinea pig heart mitochondria contained normal levels of ATPase inhibitor, they (like the rat, hamster, and mouse) showed no in situ ischemia-induced ATPase inhibition. This and other observations suggest that the lack of in situ ATPase inhibition in hearts capable of 300 or more beats/min may be due to the presence of either an in situ nonfunctional ATPase inhibitor protein or to an in situ uninhibitable form of the mitochondrial ATPase in the faster-paced hearts. Alternatively, the mitochondria of the fast-paced hearts may be insulated somehow against the cytosolic acidosis which develops during ischemia and which triggers the ATPase inhibition in the slow heart-rate hearts. In the faster paced hearts, ATP hydrolysis does not appear to be regulated by inhibitor binding to the ATPase under nonenergizing conditions.

Regulation of Mitochondrial ATP Synthase Activity in Human Myocardium

“…ATP synthase capacity in control cells incubated in the abovementioned centrifugation buffer without any further additions was 14 m-units/mg of protein (mean, n = 12). This value is of the same order of magnitude as observed in previous studies [21,22]. No significant difference in the ATP synthase capacity could be observed in the two hearts where both atrium and ventricle were examined.…”

“…This regulatory protein has been found in human hearts [22]. In isolated mitochondria IF, has been shown to respond to the potential across the mitochondrial inner membrane [25,26], binding to ATP synthase when the potential is low as in uncoupled or anoxic mitochondria.…”

From ATP to PTP and Back

“…124 Consistently, both in vitro and in vivo experimental models demonstrated that during ischemia the ATPase activity is (at least partially) inhibited by the reversible binding of IF 1 , thus mitigating ATP depletion. Indeed, in ischemic hearts of dog, 161 goat 162 and rabbit 163 the loss of ATPase activity correlates with an increased IF 1 content. Down-regulation of F-ATP synthase activity is also observed in anoxic cardiomyocytes, although the IF 1 contents were not measured.…”

Pharmacological Profile of the Selective Mitochondrial F1F0 ATP Hydrolase Inhibitor BMS‐199264 in Myocardial Ischemia

“…IF-1 in the heart is expressed differently in several mammalian species, and this has been subdivided into "fast heart rate species" (rat, mice, and birds) that express low levels of IF-1 and "slow heart rate species" (dogs and rabbits) that express high levels of IF-1 [10,[47][48][49]. It is presently unclear how these differences can affect the pathogenesis of ischemia in the different species.…”