ReviewRole of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease
Introduction
Phospholipids play multiple roles in biological membranes. They define the essential membrane permeability barrier of the cell, modulate the functional properties of membrane-associated activities, provide a matrix for the assembly and function of a variety of catalytic processes. Phospholipids may undergo to oxidative damage in their acyl chains due to oxygen radical attack. This leads to changes in structural characteristics and dynamics of the lipid bilayer with functional impairment in membrane fluidity, ion permeability, passive electric properties, membranous enzyme activity and cell signalling [1].
Among phospholipid species, cardiolipin (CL) has interesting chemical and structural characteristics, being highly acid and having a head group (glycerol) that is esterified to two phosphatidyl glyceride backbone fragments rather than one. Cardiolipin has also a highly specialized physiological distribution, being almost exclusively located in the inner membrane of mitochondria where it is biosynthesized [2], [3], [4]. Growing evidence indicate that CL plays a pivotal role in the regulation of mitochondrial bioenergetics, optimizing the activities of key mitochondrial inner membrane proteins involved in oxidative phosphorylation [5], [6], [7]. Alterations in the structure and/or content of this phospholipid are responsible for mitochondrial dysfunction in a variety of pathological settings [8], [9], [10], [11], [12], [13]. Due to its high content of unsaturated fatty acids and to its location near the site of reactive oxygen species (ROS) production, CL is particularly susceptible to peroxidative attack by ROS. CL peroxidation has been shown to play a critical role in several physiopathological situations [14], [15], [16], [17], [18] as well as in cell death [19], [20], [21], [22], [23], [24], [25], [26], [27].
Under physiological conditions Ca2+ is beneficial for mitochondrial function. However, supraphysiological accumulation of Ca2+ in mitochondria may have deleterious effect on mitochondrial function and physiology [28], [29], [30]. Some negative effects of Ca2+ on mitochondrial function are linked to ROS production and CL peroxidation [30], [31]. In the present review, we discuss several aspects of the interplay among Ca2+, ROS and cardiolipin peroxidation in mitochondrial dysfunction and disease.
Section snippets
Mitochondrial cardiolipin distribution
In eukaryotes, CL is biosynthesized from phosphatidylglycerol and cytidinediphosphate–diacylglycerol by CL synthase [3], [32]. This biosynthetic process, which takes place at the level of the inner mitochondrial membrane, appears to be highly regulated. The fatty acyl chain composition of CL is highly specific. In most mammalian tissues (heart, skeletal muscle, liver and kidney) CL contains predominantly linoleic acid (18:2) [4]. In heart mitochondria, linoleic acid constitutes 80–90% of CL
Role of cardiolipin in mitochondrial bioenergetics
Due to its location mainly on the inner mitochondrial membrane, CL has been shown to interact with a number of inner mitochondrial membrane proteins including the electron transport chain complexes involved in oxidative phosphorylation [4]. Indeed, CL is required for optimal activity of complex I (NADH ubiquinone oxidoreductase) [38], [39], [40], Complex III (ubiquinone cytochrome c oxidoreductase) [38], [41], [42], complex IV (cytochrome c oxidase) [6], [43] and complex V (ATP synthase) [44].
Cardiolipin changes in mitochondria
Due to the central role of CL in mitochondrial bioenergetics, it could be predicted that any alteration in the CL structure, content and composition may result in mitochondrial dysfunction with subsequent implications in mitochondrial physiopathology. Alterations in the content and/or composition of CL have been shown to be responsible for mitochondrial dysfunction in a variety of pathological settings [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. Alterations in mitochondrial
ROS and cardiolipin peroxidation
Reactive oxygen species (ROS) include a variety of molecules and free radicals, physiologically generated from the metabolism of molecular oxygen. Superoxide anion, the product of a one-electron reduction of oxygen, is the precursor of most ROS and a mediator in oxidative chain reactions. The product, peroxinitrite, is also a very powerful oxidant. Most estimates indicate that the majority of intracellular ROS production is derived from mitochondria. The production of mitochondrial superoxide
Cardiolipin peroxidation and mitochondrial respiratory chain complexes
As mentioned above, CL molecules are required for functional activity of a number of inner mitochondrial membrane proteins, including respiratory chain complexes involved in oxidative phosphorylation. Thus, oxidative damage to CL may have deleterious effects in mitochondrial function. Indeed. exposure of heart submitochondrial particles to mitochondrial-mediated ROS generation or ROS generating system such as xanthine/xanthine oxidase system, results in a marked loss of complex I. III and IV
Cardiolipin peroxidation and diseases
Emerging insights have linked CL oxidation/depletion to a variety of diseases and physiopathological settings. In fact, a series of studies carried out in several laboratories have demonstrated defects in the functioning of respiratory chain complexes linked to oxidation/depletion of mitochondrial CL, in various tissues of animals under a variety of diseases and physiopathological states, including heart ischemia/reperfusion [1], [14], [15], [70], hyper- and hypothyroid states [8], [9],
Ca2+ and mitochondria
The primary role of Ca2+ in mitochondria is the stimulation of the process of oxidative phosphorylation [28], [29], [30]. Thus, any perturbation in mitochondrial and cytosolic Ca2+ homeostasis may have important implications for mitochondrial and cell function [28], [29], [30]. Ca2+ entry in isolated heart mitochondria occurs via the Ca2+ uniporter and efflux via the Na+/Ca2+ exchanger. The Ca2+ uniporter is sensitive to ruthenium red and is highly dependent on the mitochondrial membrane
Ca2+ and mitochondrial permeability transition pore (MPTP)
Under physiological condition, the mitochondrial inner membrane is almost impermeable to metabolites and ions, however, under conditions of high matrix [Ca2+], especially when associated with enhanced ROS production, high phosphate and low adenine nucleotide concentrations, a non-specific pore opens which allows free passage of any molecules of <1.5 kDa, thus disrupting the permeability barrier of the inner mitochondrial membrane. This leads to the disruption of ionic homeostasis and uncoupling
Synergistic effect of Ca2+ and peroxidized cardiolipin on MPTP opening
Recently, we have shown that treatment of rat heart mitochondria with micromolar concentrations of peroxidized CL, in the presence of Ca2+, results in a concentration-dependent matrix swelling, mitochondrial membrane potential (ΔΨ) collapse, release of preaccumulated Ca2+ and release of mitochondrial cytochrome c [87]. These effects were not observed with non-oxidized CL. All these events were inhibited by cyclosporine A and bongkrekic acid, both typical inhibitors of MPTP induction. Together,
Ca2+ and peroxidized cardiolipin in MPTP opening in heart ischemia/reperfusion
In recent years, evidence has been accumulated supporting a crucial role of MPTP in cardiomyocytes cell death during ischemia/reperfusion (for review see [91]). Biochemical and pharmacological approaches indicate that MPTP remains closed during ischemia and opens at the onset of reperfusion. Among the potential mechanisms responsible for the MPTP opening during reperfusion, mitochondrial Ca2+ overload has received particular attention [92]. Exposure of mitochondria to Ca2+ in high micromolar
Cardiolipin peroxidation and Ca2+ in mitochondrial cytochrome c release and apoptosis
Mitochondria play a crucial role in the regulation of apoptotic cell death [22], [23], [24], [25]. Release of cytochrome c from mitochondria appears to be a central event in the induction of the apoptotic cascade that ultimately leads to programmed cell death. Nevertheless, the mechanism underlying cytochrome c release from mitochondria, that triggers caspase activation, is still not fully understood. Ca2+, ROS and cardiolipin appear to play a coordinated role in this process.
Cytochrome c, a
Conclusions
There is now a growing body of evidence indicating that CL has an active role in several processes involved in mitochondrial bioenergetics, especially those related to oxidative phosphorylation and coupled respiration. CL is also emerging as a key player in the regulation of several of the mitochondrial steps of cell death and in mitochondrial dynamics. In recent years, numerous studies have demonstrated mitochondrial dysfunction associated with CL abnormalities in several tissues in a variety
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