Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease

doi:10.1016/j.ceca.2009.03.012

Cell Calcium

Volume 45, Issue 6, June 2009, Pages 643-650

https://doi.org/10.1016/j.ceca.2009.03.012 Get rights and content

Abstract

Cardiolipin is a unique phospholipid which is almost exclusively located at the level of the inner mitochondrial membrane where it is biosynthesized. This phospholipid is known to be intimately involved in several mitochondrial bioenergetic processes. In addition, cardiolipin also has active roles in several of the mitochondrial-dependent steps of apoptosis and in mitochondrial membrane dynamics. Alterations in cardiolipin structure, content and acyl chains composition have been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including ischemia/reperfusion, different thyroid states, diabetes, aging and heart failure. Cardiolipin is particularly susceptible to ROS attack due to its high content of unsaturated fatty acids. Oxidative damage to cardiolipin would negatively impact the biochemical function of the mitochondrial membranes altering membrane fluidity, ion permeability, structure and function of components of the mitochondrial electron transport chain, resulting in reduced mitochondrial oxidative phosphorylation efficiency and apoptosis. Diseases in which mitochondrial dysfunction has been linked to cardiolipin peroxidation are described. Ca²⁺, particularly at high concentrations, appears to have several negative effects on mitochondrial function, some of these effects being linked to CL peroxidation. Cardiolipin peroxidation has been shown to participate, together with Ca²⁺, in mitochondrial permeability transition. In this review, we provide an overview of the role of CL 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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ReviewRole of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease

Abstract

Introduction

Section snippets

Mitochondrial cardiolipin distribution

Role of cardiolipin in mitochondrial bioenergetics

Cardiolipin changes in mitochondria

ROS and cardiolipin peroxidation

Cardiolipin peroxidation and mitochondrial respiratory chain complexes

Cardiolipin peroxidation and diseases

Ca2+ and mitochondria

Ca2+ and mitochondrial permeability transition pore (MPTP)

Synergistic effect of Ca2+ and peroxidized cardiolipin on MPTP opening

Ca2+ and peroxidized cardiolipin in MPTP opening in heart ischemia/reperfusion

Cardiolipin peroxidation and Ca2+ in mitochondrial cytochrome c release and apoptosis

Conclusions

Lipid hydroperoxide generation, turnover, and effector action in biological systems

J. Lipid Res.

Lipids of mitochondria

Biochim. Biophys. Acta

Mammalian cardiolipin biosynthesis

Methods Enzymol.

The biosynthesis and functional role of cardiolipin

Prog. Lipid Res.

Cardiolipins and biomembrane function

Biochim. Biophys. Acta

Functional binding of cardiolipin to cytochrome c oxidase

J. Bioenerg. Biomembr.

Cardiolipin, the heart of mitochondrial metabolism

Cell. Mol. Life Sci.

Decreased cytochrome oxidase activity and changes in phospholipids in heart mitochondria from hypothyroid rats

Arch. Biochem. Biophys.

Enhanced cytochrome oxidase activity and modification of lipids in heart mitochondria from hyperthyroid rats

Biochim. Biophys. Acta

Age-dependent decline in the cytochrome c oxidase activity in rat heart mitochondria: role of cardiolipin

FEBS Lett.

Lipid peroxidation and alterations to oxidative metabolism in mitochondria isolated from rat heart subjected to ischemia and reperfusion

Free Radic. Biol. Med.

Role of cardiolipin alterations in mitochondrial dysfunction and disease

Am. J. Physiol. Cell Physiol.

Mitochondrial dysfunction in rat with nonalcoholic fatty liver Involvement of complex I, reactive oxygen species and cardiolipin

Biochim. Biophys. Acta

Decreased complex III activity in mitochondria isolated from rat heart subjected to ischemia and reperfusion: role of reactive oxygen species and cardiolipin

FASEB J.

Decrease in mitochondrial complex I activity in ischemic/reperfused rat heart: involvement of reactive oxygen species and cardiolipin

Circ. Res.

Loss of cardiac tetralinoleoyl cardiolipin in human and experimental heart failure

J. Lipid Res.

Cardiolipin as an oxidative target in cardiac mitochondria in the aged rat

Biochim. Biophys. Acta

Oxidative stress and mitochondrial dysfunction in neurodegeneration; cardiolipin a critical target?

Biochim. Biophys. Acta

Role of reactive oxygen species and cardiolipin in the release of cytochrome c from mitochondria

FASEB J.

Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors

Nat. Chem. Biol.

Loss of cardiolipin and mitochondria during programmed neuronal death: evidence of a role for lipid peroxidation and autophagy

Neuroscience

Mitochondria, oxidative stress and cell death

Apoptosis

Reactive oxygen species in mitochondria-mediated cell death

Drug Metab. Rev.

Interplay between bax, reactive oxygen species production, and cardiolipin oxidation during apoptosis

Biochem. Biophys. Res. Commun.

Oxidative lipidomics of apoptosis: redox catalytic interactions of cytochrome c with cardiolipin and phosphatidylserine

Free Radic. Biol. Med.

Cardiolipin and apoptosis

Biochim. Biophys. Acta

Cardiolipin: setting the beat of apoptosis

Apoptosis

Mitochondria and Ca(2+) in cell physiology and pathophysiology

Cell Calcium

Mitochondrial Ca2+ and the heart

Cell Calcium

Calcium, ATP, and ROS: a mitochondrial love-hate triangle

Am. J. Physiol. Cell Physiol.

Ca2+-induced reactive oxygen species production promotes cytochrome c release from rat liver mitochondria via mitochondrial permeability transition (MPT)-dependent and MPT-independent mechanisms: role of cardiolipin

J. Biol. Chem.

Cardiolipin synthase from mammalian mitochondria

Biochim. Biophys. Acta

Review
Role of cardiolipin peroxidation and Ca²⁺ in mitochondrial dysfunction and disease

Ca²⁺ and mitochondria

Ca²⁺ and mitochondrial permeability transition pore (MPTP)

Synergistic effect of Ca²⁺ and peroxidized cardiolipin on MPTP opening

Ca²⁺ and peroxidized cardiolipin in MPTP opening in heart ischemia/reperfusion

Cardiolipin peroxidation and Ca²⁺ in mitochondrial cytochrome c release and apoptosis

Mitochondrial Ca²⁺ and the heart

Ca²⁺-induced reactive oxygen species production promotes cytochrome c release from rat liver mitochondria via mitochondrial permeability transition (MPT)-dependent and MPT-independent mechanisms: role of cardiolipin