Abstract
CDP diacylglycerol synthase (CDS) catalyses the conversion of phosphatidic acid (PA) to CDP-diacylglycerol, an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol (PI). CDS activity has been identified in mitochondria and endoplasmic reticulum of mammalian cells apparently encoded by two highly-related genes, CDS1 and CDS2. Cardiolipin is exclusively synthesised in mitochondria and recent studies in cardiomyocytes suggest that the peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1α and β) serve as transcriptional regulators of mitochondrial biogenesis and up-regulate the transcription of the CDS1 gene. Here we have examined whether CDS1 is responsible for the mitochondrial CDS activity. We report that differentiation of H9c2 cells with retinoic acid towards cardiomyocytes is accompanied by increased expression of mitochondrial proteins, oxygen consumption, and expression of the PA/PI binding protein, PITPNC1, and CDS1 immunoreactivity. Both CDS1 immunoreactivity and CDS activity were found in mitochondria of H9c2 cells as well as in rat heart, liver and brain mitochondria. However, the CDS1 immunoreactivity was traced to a peripheral p55 cross-reactive mitochondrial protein and the mitochondrial CDS activity was due to a peripheral mitochondrial protein, TAMM41, not an integral membrane protein as expected for CDS1. TAMM41 is the mammalian equivalent of the recently identified yeast protein, Tam41. Knockdown of TAMM41 resulted in decreased mitochondrial CDS activity, decreased cardiolipin levels and a decrease in oxygen consumption. We conclude that the CDS activity present in mitochondria is mainly due to TAMM41, which is required for normal mitochondrial function.
Highlights
The heart has the highest levels of cardiolipin; it comprises as much as 15–20% of the entire phospholipid phosphorus mass of that organ [1]
Differentiation of H9c2 cells with 1% fetal calf serum (FCS) was sufficient to induce increases in cytochrome c oxidase subunit IV (COXIV), GRP75 (75 kDa Glucose-regulated protein), and cytochrome c indicating an increase in mitochondrial biogenesis and/or functionality, retinoic acid treatment was required for expression of Troponin I
Using a commercial antibody suggested that this was due to CDPdiacylglycerol synthase 1 (CDS1), we provide compelling evidence that this activity is not due to CDS1 but due to a peripheral protein, TAMM41
Summary
The heart has the highest levels of cardiolipin; it comprises as much as 15–20% of the entire phospholipid phosphorus mass of that organ [1] This reflects the high mitochondrial density, and in cardiomyocytes there are several thousand mitochondria that are arranged in a regular pattern. The transcriptional regulators, PGC-1α and β have been shown to serve as master regulators of mitochondrial biogenesis and function [4,5] and in mice, combined deficiency of both revealed cardiolipin deficiency [6]. This phenotype was correlated with PGC-1α-mediated transcriptional control of CDPdiacylglycerol synthase 1 (CDS1), an enzyme that catalyses the conversion of PA to CDP-DG, an essential intermediate step in the biosynthesis of cardiolipin and phosphatidylinositol. Two homologous genes of CDS (CDS1 and CDS2) have been cloned that are 73% identical and 92% similar [7,8,9]
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Schedule a callMore From: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
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