Evaluation of cardiolipin nanodisks as lipid replacement therapy for Barth syndrome

Nikita Ikon,Jennifer Shearer,O Robert,Fong-Fu Hsu,M Trudy,Robert O Ryan,Trudy M Forte

doi:10.7555/jbr.32.20170094

Nikita Ikon, Jennifer Shearer + Show 5 more

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https://doi.org/10.7555/jbr.32.20170094

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Abstract

Barth syndrome (BTHS) is a mitochondrial disorder characterized by cardiomyopathy and skeletal muscle weakness. Disease results from mutations in the tafazzin (TAZ) gene, encoding a phospholipid transacylase. Defective tafazzin activity results in an aberrant cardiolipin (CL) profile. The feasibility of restoring the intracellular CL profile was tested by in vivo administration of exogenous CL in nanodisk (ND) delivery particles. Ninety mg/kg CL (as ND) was administered to doxycycline-inducible taz shRNA knockdown (KD) mice once a week. After 10 weeks of CL-ND treatment, the mice were sacrificed and tissues harvested. Liquid chromatography-mass spectrometry of extracted lipids revealed that CL-ND administration failed to alter the CL profile of taz KD or WT mice. Thus, although CL-ND were previously shown to be an effective means of delivering CL to cultured cells, this effect does not extend to an in vivo setting. We conclude that CL-ND administration is not a suitable therapy option for BTHS.

Highlights

Barth Syndrome (BTHS) is a rare, life threatening Xlinked recessive disorder characterized by cardiomyopathy, skeletal muscle weakness, low weight gain, neutropenia, and 3-methylglutaconic aciduria[1]
No CL concentration-dependent differences were observed in the levels of creatinine or blood urea nitrogen (BUN) and all values were within the normal range, consistent with normal kidney function
ND technology has been exploited for numerous applications including: packaging transmembrane proteins in a native-like membrane environment, solubilization of hydrophobic biomolecules, and as a transport vehicle for contrast agents used in magnetic resonance imaging of atherosclerotic lesions[15]

Summary

Introduction

Barth Syndrome (BTHS) is a rare, life threatening Xlinked recessive disorder characterized by cardiomyopathy, skeletal muscle weakness, low weight gain, neutropenia, and 3-methylglutaconic aciduria[1]. Loss of tafazzin activity leads to a deficiency in cardiolipin (CL), an important phospholipid component of the mitochondrial inner membrane (IM). Additional changes include increased CL molecular species heterogeneity and accumulation of monolyso (ML) CL[5]. Given the key structural role CL plays in the IM of mitochondria[6], it is not surprising that BTHS subjects manifest ultrastructural changes to this organelle[7], as well as defective energy metabolism, in cardiac tissue and skeletal muscle[8–9]. Heart and skeletal muscle mitochondria are highly enriched in a single CL molecular species, tetralinoleoyl CL[10]. Establishment and maintenance of this molecular species composition is dependent upon acyl chain remodeling reactions that involve tafazzin transacylase activity[11]. When tafazzin is missing or defective, major changes in CL content and composition occur

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