Abstract
The mitochondrial phospholipid cardiolipin is required for optimal mitochondrial respiration. In this study, cardiolipin molecular species and cytochrome oxidase (COx) activity were studied in interfibrillar (IF) and subsarcolemmal (SSL) cardiac mitochondria from Spontaneously Hypertensive Heart Failure (SHHF) and Sprague-Dawley (SD) rats throughout their natural life span. Fisher Brown Norway (FBN) and young aortic-constricted SHHF rats were also studied to investigate cardiolipin alterations in aging versus pathology. Additionally, cardiolipin was analyzed in human hearts explanted from patients with dilated cardiomyopathy. A loss of tetralinoleoyl cardiolipin (L(4)CL), the predominant species in the healthy mammalian heart, occurred during the natural or accelerated development of heart failure in SHHF rats and humans. L(4)CL decreases correlated with reduced COx activity (no decrease in protein levels) in SHHF cardiac mitochondria, but with no change in citrate synthase (a matrix enzyme) activity. The fraction of cardiac cardiolipin containing L(4)CL became much lower with age in SHHF than in SD or FBN mitochondria. In summary, a progressive loss of cardiac L(4)CL, possibly attributable to decreased remodeling, occurs in response to chronic cardiac overload, but not aging alone, in both IF and SSL mitochondria. This may contribute to mitochondrial respiratory dysfunction during the pathogenesis of heart failure.
Highlights
The mitochondrial phospholipid cardiolipin is required for optimal mitochondrial respiration
CL alterations in Spontaneously Hypertensive Heart Failure (SHHF) rat heart mitochondria To examine the time course of CL alterations in the progression to heart failure (HF), the CL species profile was examined in cardiac mitochondria obtained at various ages throughout the natural life span of the SHHF rat (Fig. 1)
Given the potential for different effects of cardiac pathology on the two populations of mitochondria in the heart [6, 23, 33], we examined the CL profile in both SSL and IF mitopositive correlation existed between L4CL content and cytochrome oxidase (COx) activity in both SSL and IF mitochondria (Fig. 2C, D)
Summary
The mitochondrial phospholipid cardiolipin is required for optimal mitochondrial respiration. A loss of tetralinoleoyl cardiolipin (L4CL), the predominant species in the healthy mammalian heart, occurred during the natural or accelerated development of heart failure in SHHF rats and humans. A progressive loss of cardiac L4CL, possibly attributable to decreased remodeling, occurs in response to chronic cardiac overload, but not aging alone, in both IF and SSL mitochondria This may contribute to mitochondrial respiratory dysfunction during the pathogenesis of heart failure.—Sparagna, G. In humans [2, 3] and animal models of HF [4], reduced activities of mitochondrial respiratory complexes are paralleled by decreases in oxidative phosphorylation potential [5, 6] and a loss of high-energy phosphate content in the heart [7, 8]. Chicco contributed to this work. 2 To whom correspondence should be addressed
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