Emerging roles of cardiolipin remodeling in mitochondrial dysfunction associated with diabetes, obesity, and cardiovascular diseases

Yuguang Shi

doi:10.1016/s1674-8301(10)60003-6

Abstract

Cardiolipin (CL) is a phospholipid exclusively localized in inner mitochondrial membrane where it is required for oxidative phosphorylation, ATP synthesis, and mitochondrial bioenergetics. The biological functions of CL are thought to depend on its acyl chain composition which is dominated by linoleic acids in metabolically active tissues. This unique feature is not derived from the de novo biosynthesis of CL, rather from a remodeling process that involves in phospholipases and transacylase/acyltransferase. The remodeling process is also believed to be responsible for generation of CL species that causes oxidative stress and mitochondrial dysfunction. CL is highly sensitive to oxidative damages by reactive oxygen species (ROS) due to its high content in polyunsaturated fatty acids and location near the site of ROS production. Consequently, pathological remodeling of CL has been implicated in the etiology of mitochondrial dysfunction commonly associated with diabetes, obesity, heart failure, neurodegeneration, and aging that are characterized by oxidative stress, CL deficiency, and abnormal CL species. This review summarizes recent progresses in molecular, enzymatic, lipidomic, and metabolic studies that support a critical regulatory role of pathological CL remodeling as a missing link between oxidative stress and mitochondrial dysfunction in metabolic diseases and aging.

Highlights

Mitochondrial dysfunction has recently been identified as a common metabolic defect associated with obesity and its metabolic complications[1, 2]
A number of early studies suggest that mitochondrial oxidative function was compromised in diabetic and prediabetic humans as evidenced by reduced levels of fatty acid oxidation[3], insulin-stimulated ATP synthesis[4,5,6], and expression of genes involved in oxidative phosphorylation[7]
Pathological CL remodeling has been implicated in etiology of mitochondrial dysfunction associated with a host of pathophysiological conditions including diabetes, obesity, heart failure, hyperthyroidism, neurodegeneration, and aging, all of which are characterized by increased levels of oxidative stress, CL deficiency, and enrichment of docosahexaenoic acid (DHA) content in CL[22,23,24,25,26]

Summary

INTRODUCTION

Mitochondrial dysfunction has recently been identified as a common metabolic defect associated with obesity and its metabolic complications[1, 2]. Cardiolipin(CL) is polyglycerophospholipid exclusively localized in the mitochondria where it regulates mitochondrial function and oxidative stress in species from yeast to mammals[14,15,16] This role is mediated by the acyl composition of the side chains of CL, which is dominated by linoleic acid in insulin sensitive tissues[17]. In comparison to the MLCL AT, ALCAT1 lacks preference for linoleic acid as substrate, suggesting a possible role of ALCAT1 in pathological remodeling of CL[19, 20] This is corroborated by our recent reports that ALCAT1 expression is up-regulated in mammalian cells exhibiting tetralinoleoyl-CL deficiency and in heart and liver of mice suffering from oxidative stress induced by hyperthyroidism[43]. In support of a key role of CL peroxidation in mitochondrial dysfunction, CL is the only phospholipid that undergoes oxidation during the onset of apoptosis[21]

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Findings

CONCLUSION