for Cardiolipin Biosynthesis in Mitochondria

Since the phospholipid cardiolipin (CL) is required for function of the mitochondrial respiratory chain, we examined the dynamics of CL synthesis in growing Hela cells immediately after and 12 h post-fusion.

Biosynthesis of Cardiolipin in Plant Mitochondria | …

A mitochondrial phosphatase required for cardiolipin biosynthesis: ..

The mechanism of cardiolipin biosynthesis in liver mitochondria ..

CDP-diacylglycerol (CDP-DAG) is central to the phospholipid biosynthesis pathways in cells. A prevailing view is that only one CDP-DAG synthase named Cds1 is present in both the endoplasmic reticulum (ER) and mitochondrial inner membrane (IM) and mediates generation of CDP-DAG from phosphatidic acid (PA) and CTP. However, we demonstrate here by using yeast Saccharomyces cerevisiae as a model organism that Cds1 resides in the ER but not in mitochondria, and that Tam41, a highly conserved mitochondrial maintenance protein, directly catalyzes the formation of CDP-DAG from PA in the mitochondrial IM. We also find that inositol depletion by overexpressing an arrestin-related protein Art5 partially restores the defects of cell growth and CL synthesis in the absence of Tam41. The present findings unveil the missing step of the cardiolipin synthesis pathway in mitochondria as well as the flexibile regulation of phospholipid biosynthesis to respond to compromised CDP-DAG synthesis in mitochondria.

Biosynthesis of cardiolipin in liver ..

N2 - CDP-diacylglycerol (CDP-DAG) is central to the phospholipid biosynthesis pathways in cells. A prevailing view is that only one CDP-DAG synthase named Cds1 is present in both the endoplasmic reticulum (ER) and mitochondrial inner membrane (IM) and mediates generation of CDP-DAG from phosphatidic acid (PA) and CTP. However, we demonstrate here by using yeast Saccharomyces cerevisiae as a model organism that Cds1 resides in the ER but not in mitochondria, and that Tam41, a highly conserved mitochondrial maintenance protein, directly catalyzes the formation of CDP-DAG from PA in the mitochondrial IM. We also find that inositol depletion by overexpressing an arrestin-related protein Art5 partially restores the defects of cell growth and CL synthesis in the absence of Tam41. The present findings unveil the missing step of the cardiolipin synthesis pathway in mitochondria as well as the flexibile regulation of phospholipid biosynthesis to respond to compromised CDP-DAG synthesis in mitochondria.

T1 - The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis
The organization of the cardiolipin synthesis complex and its interactions with mitochondrial proteins

Role of cardiolipin alterations in mitochondrial dysfunction and ..

Taken together, the evidence presented here leads us to propose that the binding of SLP-2 to cardiolipin recruits PHBs, helping to form cardiolipin-enriched membrane microdomains in which the respiratory chain components are optimally assembled. The formation of these microdomains is likely the result of the self-oligomerizing properties of SLP-2 (). The increase in respiratory chain function may then induce further cardiolipin synthesis through its effect on the pH gradient across the mitochondrial inner membrane (), enhancing mitochondrial biogenesis. The result of this proposed mechanism is the provision of the enhanced mitochondrial function required for an optimal T cell response.

Pharmacology & Pharmaceutical Medicine

Upregulation of SLP-2 expression increases cardiolipin synthesis and mitochondrial biogenesis. Recent evidence indicates that these two processes are tightly coordinated (), likely through the PHB functional interactome, which includes genes involved in phospholipid synthesis, such as Ups1, whose deletion, in yeast, translates into a marked decrease in cardiolipin content (). Although we have not shown a direct interaction among PHBs, SLP-2, and cardiolipin, our data suggest that SLP-2 may bring PHBs to cardiolipin and may contribute to the organization of cardiolipin-enriched microdomains in the mitochondrial inner membrane (). Data from our laboratory using T cell-specific SLP-2 knockout mice seem to corroborate this model (D. A. Christie et al., unpublished data). This possible mechanism accommodates the upregulation of both SLP-2 and PHBs during T cell activation () and the detection of both proteins in detergent-insoluble microdomains of cell membranes (i.e., cardiolipin-enriched microdomains in the mitochondrial inner membrane and cholesterol-enriched microdomains in the plasma membrane) (, , , ). In this context, an increase in SLP-2 levels as a result of cell activation would increase the interaction of PHBs with cardiolipin in the mitochondrial inner membrane and activate the PHB functional interactome, leading to de novo cardiolipin synthesis.

Targeting mitochondrial cardiolipin and the cytochrome …

Next, we examined how upregulation of SLP-2 expression may induce mitochondrial biogenesis. Emerging data suggest that mitochondrial biogenesis is coordinated by a mechanism involving PHB-1 and -2 (, ). These proteins localize within phospholipid-enriched, detergent-insoluble microdomains in mitochondrial membranes, and their functional interactome includes genes such as Ups1 and Gep1, which are linked to the synthesis of the mitochondrial membrane phospholipids cardiolipin and phosphatidylethanolamine, respectively (, ). We noticed that Saccharomyces cerevisiae PHB-2 has a putative transmembrane domain (as predicted by the transmembrane hidden mark or model [TMHMM] algorithm []), but neither mouse nor human PHBs have such a domain. Of interest, S. cerevisiae does not have a homolog of SLP-2, the closest being PHB-1, with a Clustal W score of 15 (). This suggested that, in mammals, SLP-2 may act to link PHBs and phospholipid-enriched detergent-insoluble microdomains in mitochondrial membranes. Such a possibility is consistent with the observations that PHBs are upregulated in parallel with SLP-2 during activation () (b) and that SLP-2 interacts with PHBs ().