The Role of Cardiolipin in Cardiovascular Health

Abstract

Cardiolipin (CL), the signature phospholipid of mitochondrial membranes, is crucial for both mitochondrial function and cellular processes outside of the mitochondria. The importance of CL in cardiovascular health is underscored by the life-threatening genetic disorder Barth syndrome (BTHS), which manifests clinically as cardiomyopathy, skeletal myopathy, neutropenia, and growth retardation. BTHS is caused by mutations in the gene encoding tafazzin, the transacylase that carries out the second CL remodeling step. In addition to BTHS, CL is linked to other cardiovascular diseases (CVDs), including cardiomyopathy, atherosclerosis, myocardial ischemia-reperfusion injury, heart failure, and Tangier disease. The link between CL and CVD may possibly be explained by the physiological roles of CL in pathways that are cardioprotective, including mitochondrial bioenergetics, autophagy/mitophagy, and mitogen activated protein kinase (MAPK) pathways. In this review, we focus on the role of CL in the pathogenesis of CVD as well as the molecular mechanisms that may link CL functions to cardiovascular health.

Known unknowns of cardiolipin signaling: The best is yet to come

“…Structurally, the four acyl chains of CL coupled with the double-negatively charged polar end provide CL with a “conical” shape, with the polar region being the cone cusp, and the flexible and variable acyl chains being the base of the “cone”. The length, saturation and oxidation of these side chains, provide differential influences on the shape, binding, function and stability of CL [35, 48, 81, 82]. This “conical” shaped and double negatively charged CL is asymmetrically distributed in the IMM with a higher concentration of CL on the inner side of the IMM.…”

“…This includes signaling during cell death, mitophagy, innate immunity and potentially many hereto unknown signaling functions. With increasing signaling complexity, the potential for defects derived from CL biosynthesis resulting in pathology is already apparent in Barth Syndrome [33, 35, 46-48] and it is likely other diseases linked to CL structure, location and stability may subsequently be defined.…”

Distinct membrane properties are differentially influenced by cardiolipin content and acyl chain composition in biomimetic membranes

“…Three well-identified pathological alterations to CL include the loss of CL content, peroxidation, and remodeling of acyl chains [10;12;15;22]. Loss of CL content could arise from either enhanced CL degradation, due to an up-regulation in phospholipase activity, or by a decrease in de novo synthesis as a result of compromised functions of the enzymes involved in CL synthesis [10;11].…”

Fuel availability and fate in cardiac metabolism: A tale of two substrates

“…Thus, aging hearts display increased levels of saturated FAs in membrane phospholipids, a feature that has been associated with decreased membrane fluidity and transport [5]. In addition, reduced mitochondrial content of cardiolipin and alterations in cardiolipin FA composition observed in both aging hearts and the genetic disorder, Barth syndrome, have been linked to disturbances of the electron transport chain assembly and activity, decreased ATP production and increased formation of reactive oxygen species (ROS), and defective protein import and mitophagy, which ultimately lead to cardiovascular dysfunction [6]. …”