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

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Phosphatidylethanolamine (PE) is essential for mitochondrial respiration in yeast, Saccharomyces cerevisiae , whereas the most abundant mitochondrial phospholipid, phosphatidylcholine (PC), is largely dispensable. Surprisingly, choline (Cho), which is a biosynthetic precursor of PC, has been shown to rescue the respiratory growth of mitochondrial PE-deficient yeast; however, the mechanism underlying this rescue has remained unknown. Using a combination of yeast genetics, lipid biochemistry, and cell biological approaches, we uncover the mechanism by showing that Cho rescues mitochondrial respiration by partially replenishing mitochondrial PE levels in yeast cells lacking the mitochondrial PE-biosynthetic enzyme Psd1. This rescue is dependent on the conversion of Cho to PC via the Kennedy pathway as well as on Psd2, an enzyme catalyzing PE biosynthesis in the endosome. Metabolic labeling experiments reveal that in the absence of exogenously supplied Cho, PE biosynthesized via Psd2 is mostly directed to the methylation pathway for PC biosynthesis and is unavailable for replenishing mitochondrial PE in Psd1-deleted cells. In this setting, stimulating the Kennedy pathway for PC biosynthesis by Cho spares Psd2-synthesized PE from the methylation pathway and redirects it to the mitochondria. Cho-mediated elevation in mitochondrial PE is dependent on Vps39, which has been recently implicated in PE trafficking to the mitochondria. Accordingly, epistasis experiments placed Vps39 downstream of Psd2 in Cho-based rescue. Our work, thus, provides a mechanism of Cho-based rescue of mitochondrial PE deficiency and uncovers an intricate interorganelle phospholipid regulatory network that maintains mitochondrial PE homeostasis.