Cardiolipin Remodeling in the Heart

Abstract

Cardiolipin (CL) is a mitochondrial phospholipid that fundamentally contributes to the function of many proteins in the inner mitochondrial membrane, where it is actively involved in the integrity and flux of the electron transport chain. In the heart, functional CL is linoleic acid rich, and the loss of linoleic acid content is associated with cardiac disorders including ischemia and reperfusion, heart failure, and diabetes, as well as the X-linked recessive disease, Barth syndrome. To attain its high levels of linoleic acid, newly synthesized CL must initially undergo remodeling. CL modification and depletion by pathological processes may represent a failure of this remodeling pathway or activation of an alternative "pathological remodeling" pathway that causes the substitution of higher molecular weight, polyunsaturated fatty acyl side chains such as arachidonic or docosahexaenoic acid onto CL. This remodeling may occur in response to the alteration of CL by oxidative mechanisms, but the substituted side chains can also provoke further oxidation of CL. It is increasingly thought that cardiac pathology may result, at least partially, due to changes in CL resulting from the pathological remodeling process. Dietary interventions may restore CL to its linoleic acid-rich form and improve cardiac function by redirecting the remodeling process.

Dietary macronutrients modulate the fatty acyl composition of rat liver mitochondrial cardiolipins

“…Previous studies focused on evidence that limiting an animal's 18:2 FA intake was associated with decreasing CL levels, mitochondrial dysfunction, and morbidity ( 3,8,38,45 ). These studies also showed that many FAs are not observed in CL pools (i.e., active exclusion).…”

“…Analysis of CL in hearts explanted from patients with dilated cardiomyopathy revealed a loss of tetralinoleoyl CL species ( 32 ). Surprisingly, all physiologically modifi ed scenarios appeared associated with decreased CL levels ( 3,8,32,33,37,38 ). There seemed to be no active regulation of CLs to restore homeostasis or to counteract a biased diet.…”

Myocardial Regulation of Lipidomic Flux by Cardiolipin Synthase

“…Intense investigation has focused on identifying the molecular mechanisms that sculpt CL molecular species as well as regulate and maintain CL content in the mitochondrial membrane during development, health, and disease pathogenesis (18,65). Alterations in CL content and molecular species have been demonstrated in heart failure, diabetes, Barth syndrome, myocardial ischemia, hyperthyroidism, oxidative stress, aging, and cancer (5,24,30,31,33,66).…”

The role of calcium-independent phospholipase A2 in cardiolipin remodeling in the spontaneously hypertensive heart failure rat heart

“…Second, the high prevalence of (18:2) 4 CL over other CL species is unlikely if one considers the remodeling process to be random with respect to acyl selection, which suggests that the loading of CL with 18:2 is purposeful. Lastly and most importantly, a loss of (18:2) 4 CL, along with an increase in 18:2-defi cient CL species, occurs in a number of cardiac disease states ( 6,18 ). The disease most directly associated with a loss of (18:2) 4 CL is Barth syndrome, caused by an X-linked mutation in the tafazzin gene (19)(20)(21)(22).…”

“…Neither the acyl composition of PG and CDP-DAG nor the acyl specifi city of CLS results in an enrichment of CL with 18:2 de novo; thus, nascent CL must be converted to (18:2) 4 CL through an acyl remodeling cycle. Presumably, the remodeling of CL occurs through a series of deacylation-reacylation reactions, though the details of CL remodeling in vivo remain in question ( 18,30 ). To date, three enzymes have been identifi ed that are capable of adding 18:2 to a monolysoCL (MLCL): tafazzin ( 32 ), MLCL-acyltransferase (MLCL-AT, 33 ), and acylCoAlysocardiolipin acyltransferase (ALCAT-1, 34 ).…”