Mitochondrial dysfunctions in barth syndrome

Abstract

Barth syndrome (BTHS) is a rare multisystemic genetic disorder caused by mutations in the TAZ gene. TAZ encodes a mitochondrial enzyme that remodels the acyl chain composition of newly synthesized cardiolipin, a phospholipid unique to mitochondrial membranes. The clinical abnormalities observed in BTHS patients are caused by perturbations in various mitochondrial functions that rely on remodeled cardiolipin. However, the contribution of different cardiolipin-dependent mitochondrial functions to the pathology of BTHS is not fully understood. In this review, we will discuss recent findings from different genetic models of BTHS, including the yeast model of cardiolipin deficiency that has uncovered the specific in vivo roles of cardiolipin in mitochondrial respiratory chain biogenesis, bioenergetics, intermediary metabolism, mitochondrial dynamics, and quality control. We will also describe findings from higher eukaryotic models of BTHS that highlight a link between cardiolipin-dependent mitochondrial function and its impact on tissue and organ function. © 2019 IUBMB Life, 9999(9999):1-11, 2019.

Keywords: Barth syndrome; cardiolipin; mitochondria.

Figure 1:. Cardiolipin biosynthetic pathway.

(A) CL biosynthesis occurs exclusively in the mitochondria. CL precursor, PA, is transported from the OMM to the IMM via Ups1/Mdm35 to initiate the CL biosynthetic pathway. PA is converted to PG through three subsequent enzyme-catalyzed reactions by Tam41, Pgs1, and Gep4. Crd1 biosynthesizes nascent CL (CL_p) from PG. CL_p must then be remodeled to form mature CL (CL_m) through sequential deacylation and reacylation reactions catalyzed by Cld1 and Taz1, respectively. Taz1 is localized to the OMM and the IMM facing the IMS. (B) Structures of CL_p, MLCL, and CL_m. ATP, adenosine triphosphate; ADP, adenosine diphosphate; CTP, cytidine triphosphate; PPi, pyrophosphate; CDP-DAG, cytidine diphosphate-diacylglycerol; CMP, cytidine monophosphate; PA, phosphatidic acid; CL_p, premature cardiolipin; CL_m, mature cardiolipin; MLCL, monolysocardiolipin; PG, phosphatidylglycerol; PGP, phosphatidylglycerol phosphate; G3P, glycerol-3-phosphate; PL, phospholipid; FA, fatty acid; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; IMS, intermembrane space.