Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects

Abstract

In eukaryotic cells, mitochondria are involved in a large array of metabolic and bioenergetic processes that are vital for cell survival. Phospholipids are the main building blocks of mitochondrial membranes. Cardiolipin (CL) is a unique phospholipid which is localized and synthesized in the inner mitochondrial membrane (IMM). It is now widely accepted that CL plays a central role in many reactions and processes involved in mitochondrial function and dynamics. Cardiolipin interacts with and is required for optimal activity of several IMM proteins, including the enzyme complexes of the electron transport chain (ETC) and ATP production and for their organization into supercomplexes. Moreover, CL plays an important role in mitochondrial membrane morphology, stability and dynamics, in mitochondrial biogenesis and protein import, in mitophagy, and in different mitochondrial steps of the apoptotic process. It is conceivable that abnormalities in CL content, composition and level of oxidation may negatively impact mitochondrial function and dynamics, with important implications in a variety of pathophysiological situations and diseases. In this review, we focus on the role played by CL in mitochondrial function and dynamics in health and diseases and on the potential of pharmacological modulation of CL through several agents in attenuating mitochondrial dysfunction.

Keywords: Cardiolipin; mitochondrial structure-function; pharmacological agents; physiopathology.

Figure 1

Proposed roles of cardiolipin in mitochondrial function and dynamics. Cyt c, cytochrome c; ETC, electron transport chain; IMM, inner mitochondrial membrane; mPTP, mitochondrial permeability transition pore. For details, see the text.

Figure 2

Proposed role for cardiolipin in ATP synthasome formation and mPTP opening. ANT, adenine nucleotide translocator; CL, cardiolipin; CLox, oxidized cardiolipin; Cyp D, cyclophilin D; IMM, inner mitochondrial membrane; mPTP, mitochondrial permeability transition pore; PiC, phosphate carrier. For details, see the text.

Figure 3

Cardiolipin abnormalities in diseases. I/R, ischemia/reperfusion, ROS, reactive oxygen species. For details, see the text.

Figure 4

Cardiolipin as target for pharmacological intervention in disease. ETC, electron transport chain; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species. For details, see the text.