Metabolic Alterations Caused by Defective Cardiolipin Remodeling in Inherited Cardiomyopathies

Abstract

The heart is the most energy-consuming organ in the human body. In heart failure, the homeostasis of energy supply and demand is endangered by an increase in cardiomyocyte workload, or by an insufficiency in energy-providing processes. Energy metabolism is directly associated with mitochondrial redox homeostasis. The production of toxic reactive oxygen species (ROS) may overwhelm mitochondrial and cellular ROS defense mechanisms in case of heart failure. Mitochondria are essential cell organelles and provide 95% of the required energy in the heart. Metabolic remodeling, changes in mitochondrial structure or function, and alterations in mitochondrial calcium signaling diminish mitochondrial energy provision in many forms of cardiomyopathy. The mitochondrial respiratory chain creates a proton gradient across the inner mitochondrial membrane, which couples respiration with oxidative phosphorylation and the preservation of energy in the chemical bonds of ATP. Akin to other mitochondrial enzymes, the respiratory chain is integrated into the inner mitochondrial membrane. The tight association with the mitochondrial phospholipid cardiolipin (CL) ensures its structural integrity and coordinates enzymatic activity. This review focuses on how changes in mitochondrial CL may be associated with heart failure. Dysfunctional CL has been found in diabetic cardiomyopathy, ischemia reperfusion injury and the aging heart. Barth syndrome (BTHS) is caused by an inherited defect in the biosynthesis of cardiolipin. Moreover, a dysfunctional CL pool causes other types of rare inherited cardiomyopathies, such as Sengers syndrome and Dilated Cardiomyopathy with Ataxia (DCMA). Here we review the impact of cardiolipin deficiency on mitochondrial functions in cellular and animal models. We describe the molecular mechanisms concerning mitochondrial dysfunction as an incitement of cardiomyopathy and discuss potential therapeutic strategies.

Different Lipid Signature in Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

“…It has recently been recognized that the HADHA gene encoding the α-subunit of the human mitochondrial trifunctional enzyme is crucial for cardiolipin remodeling [ 27 ]. Dysfunctional cardiolipin composition has been described in diabetic cardiomyopathy, ischemia reperfusion injury and other inherited cardiomyopathies [ 28 ]. As enzymes of mitochondrial β-oxidation are physically associated with OXPHOS in a multifunctional mitochondrial protein complex [ 8 , 29 ], we focused specifically on the CL lipid class.…”

“…We speculate that this derangement contributes to the dysregulation of mitochondrial dynamics and reduced respiration described in LCHADD but not VLCAD fibroblasts [ 15 ]. Beyond the alteration of the fusion/fission machinery, CLs are also tightly involved in the regulation of mitochondrial metabolism [ 23 , 28 , 45 , 49 , 50 , 51 ]. Since the α-subunit of MTP is required for CL remodeling, LCHADD/MTPD induced changes in CL composition likely leads to instability of mitochondrial supercomplexes, explaining impairment of previously described mitochondrial functions [ 15 ].…”

Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology

“…CL deficiency was reported to cause a defect in respiratory function and a decrease in ATP synthesis [ 74 ], an indirect demonstration of CL role in the structure of the SCs. Rieger et al [ 75 ] investigated the effect of ALCAT1 overexpression.…”

Lipidomic and Proteomic Alterations Induced by Even and Odd Medium-Chain Fatty Acids on Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

“…Our findings demonstrated that lipid remodeling also occurred in human fibroblasts of lc-FAOD after incubation with either C7 or C8 (see also Figure S2 ). Due to the importance of CL for several mitochondrial functions [ 39 , 40 , 41 ] and the fact that alteration in the composition is often associated with impaired mitochondrial metabolism [ 42 , 43 , 44 , 45 , 46 , 47 ], we mainly focused on the total content and composition of CL. The previously reported increase in CL content and altered CL composition in LCHADD fibroblasts [ 19 ] is supported by the finding of a remarkable up-regulation of components of oxidative phosphorylation (OXPHOS).…”