Dysregulation of cardiolipin biosynthesis in pediatric heart failure

Abstract

Background Cardiolipin, a unique phospholipid in the inner mitochondrial membrane, is critical for optimal mitochondrial function. CL abnormalities have been demonstrated in the failing rodent and adult human heart. The aim of this study was to determine whether abnormalities in CL content and the CL biosynthesis and remodeling pathways are present in pediatric idiopathic dilated cardiomyopathy (IDC). Methods and Results A cross-sectional analysis of myocardial tissue from 119 IDC and non-failing (NF) control samples was performed. Electrospray ionizing mass spectrometry was used to measure total CL and CL species content in LV tissue. RT-PCR was employed to measure gene expression of the enzymes in the CL biosynthesis and remodeling pathways in both the adult and pediatric heart. Significantly lower total and (18:2)4CL (the beneficial species) content was demonstrated in myocardium from pediatric patients with IDC compared to NF controls. Analysis of mitochondrial gene transcripts was used to demonstrate that there is no decrease in mitochondrial content. Expression of two biosynthesis enzymes and one remodeling enzyme was significantly lower in pediatric IDC compared to NF controls. Expression of two phospholipases involved in CL degradation were also altered, one up and one down-regulated. Except for one remodeling enzyme, these changes are unique from those in the failing adult heart. Conclusion Similar to what has been seen in adults and in a rat model of IDC, total and (18:2)4CL are lower in pediatric IDC. Unique CL species profiles are seen in heart tissue from children with IDC compared to adults. Differences in CL biosynthesis and remodeling enzyme expression likely explain the differences in CL profiles observed in IDC and implicate unique age-related mechanisms of disease.

The cardiolipin-binding peptide elamipretide mitigates fragmentation of cristae networks following cardiac ischemia reperfusion in rats

“…CL is essential for protein import, localization, and assembly, profoundly influencing mitochondrial dynamics, energetics, and network continuity 9,10 . Previous studies established oxidation and subsequent lowering of CL content across cardiac pathologies, including acute ischemia-reperfusion (I/R) 11,12 and heart failure [13][14][15] . Aside from exogenous perfusion with CL 16 , which may only be applicable in experimental settings, there are currently no therapies that can improve mitochondrial function by targeting CL.…”

Acute isoproterenol leads to age-dependent arrhythmogenesis in guinea pigs

“…Importantly, therapies that improve outcomes in adult patients with IDC fail to provide such benefits in pediatric patients with IDC (54,55,65). We have previously shown fundamental differences in the myocellular mechanisms involved in cardiac pathology between children and adults with IDC, which we propose lead to differences in response to therapies (7,38,42,63,71). Further investigation of these differences will improve understanding of both patient populations and ultimately lead to identification of age-specific targeted treatments that could improve clinical outcomes.…”

Myocardial Energy Metabolism in Non-ischemic Cardiomyopathy

“…Cardiolipin is a structurally distinct mitochondrial phospholipid with essential roles in the maintenance of mitochondrial morphology, regulation of mitochondrial protein transport and dynamics, and in maintaining the integrity and optimal activity of the ETC (Dudek and Maack, 2017;Dudek et al, 2019). Furthermore, aberrant myocardial cardiolipin content and composition, specifically reduction of the predominant tetralinoleoyl cardiolipin species, has been reported in a variety of cardiac pathologies, including idiopathic dilated cardiomyopathy (Chatfield et al, 2014), and in both human and experimental models of heart failure (Sparagna et al, 2007). As such, infantile-onset cardiomyopathy is the most common clinical feature associated with BTHS, although other phenotypic traits can include neutropenia, skeletal myopathy, exercise intolerance, 3-methylglutaconic aciduria, and pre-pubertal growth retardation (Jefferies, 2013).…”