Role of calcium-independent phospholipase A ₂ in the pathogenesis of Barth syndrome

Abstract

Quantitative and qualitative alterations of mitochondrial cardiolipin have been implicated in the pathogenesis of Barth syndrome, an X-linked cardioskeletal myopathy caused by a deficiency in tafazzin, an enzyme in the cardiolipin remodeling pathway. We have generated and previously reported a tafazzin-deficient Drosophila model of Barth syndrome that is characterized by low cardiolipin concentration, abnormal cardiolipin fatty acyl composition, abnormal mitochondria, and poor motor function. Here, we first show that tafazzin deficiency in Drosophila disrupts the final stage of spermatogenesis, spermatid individualization, and causes male sterility. This phenotype can be genetically suppressed by inactivation of the gene encoding a calcium-independent phospholipase A2, iPLA2-VIA, which also prevents cardiolipin depletion/ monolysocardiolipin accumulation, although in wild-type flies inactivation of the iPLA2-VIA does not affect the molecular composition of cardiolipin. Furthermore, we show that treatment of Barth syndrome patients' lymphoblasts in tissue culture with the iPLA2 inhibitor, bromoenol lactone, partially restores their cardiolipin homeostasis. Taken together, these findings establish a causal role of cardiolipin deficiency in the pathogenesis of Barth syndrome and identify iPLA2-VIA as an important enzyme in cardiolipin deacylation, and as a potential target for therapeutic intervention.cardiolipin ͉ Drosophila ͉ iPLA2 ͉ tafazzin

Genetic Ablation of Calcium-independent Phospholipase A2γ Leads to Alterations in Hippocampal Cardiolipin Content and Molecular Species Distribution, Mitochondrial Degeneration, Autophagy, and Cognitive Dysfunction

“…The lack of accumulation of lipids in myocardial mitochondria suggests that compensatory mechanisms for hydrolyzing cardiolipin are present in myocardial mitochondria that are not effective in hippocampus. Collectively, these results are consistent with previous evidence in Drosophila demonstrating an important role of an iPLA 2 homolog in cardiolipin remodeling (54).…”

“…Mitochondria are centrally involved in neurotransmission as well as in the metabolic plasticity necessary for neuronal survival (65). Many studies have described abnormal, compromised, or enlarged mitochondria in aging, multiple neurologic diseases, and apoptosis (49,51,53,54). Aging is associated with a decreased capacity to generate ATP by oxidative phosphorylation due primarily to diminished complex I and IV activity in mitochondria (6,64,66).…”

Dynamic simulation of cardiolipin remodeling: greasing the wheels for an interpretative approach to lipidomics

“…For example, a similar broad distribution of cardiolipin molecular species was observed between day 5 and 15 for normal mouse cardiac development (data not shown) as well as in mature mouse brain ( 16,26 ). It is interesting that this broad distribution of cardiolipin molecular species is also observed in various disease states, culture conditions, and transgenic models of enzymes that catalyze cardiolipin remodeling ( 23,(41)(42)(43)(44)(45). This suggests a common remodeling event or role of various acyltransferases, transacylases, or phospholipases involved in this stage of the remodeling process.…”

“…CL, cardiolipin. is commonly believed that acyl CoA as well as PC and PE contribute to the pool of acyl chains used for cardiolipin remodeling in mitochondria ( 20,21,23,24,38,43 ). In addition, Lands cycle remodeling utilizes the sn -2 positions of glycerophospholipids for remodeling ( 49,50 ).…”

The Role of Cardiolipin Remodeling in Mitochondrial Function and Human Diseases

“…The TAZ gene product is ubiquitously expressed and exists in several protein isoforms due to different splicing (Bione et al, 1996). Yeast complementation suggested one spliced variant of TAZ lacking exon 5 most likely represented the only physiological mRNA (Vaz et al, 2003;Xu et al, 2009). Patients with Barth syndrome exhibit abnormal CL content, such as decreased CL content, loss of dominant 18:2 fatty acyl content and loss of four linoleoyl CL (Schlame et al, 2002;Schlame et al, 2003).…”