AMP-Activated Protein Kinase α2 Deficiency Affects Cardiac Cardiolipin Homeostasis and Mitochondrial Function

Athéa, Yoni; Viollet, Benoı̂t; Matéo, Philippe; Rousseau, Delphine; Novotová, Marta; Garnier, Anne; Vaulont, Sophie; Wilding, James R.; Grynberg, Alain; Veksler, Vladimir; Hoerter, Jacqueline; Ventura‐Clapier, Renée

doi:10.2337/db06-0187

Cited by 50 publications

(58 citation statements)

References 52 publications

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“…A recent review from the laboratory that identified TAZ as the CL transacylase suggested that although evidence indicates that tafazzin clearly and specifically remodels mitochondrial CL with linoleate, the idea that tafazzin determines the fatty acid profile of CL is conceptually problematic and contradicts experimental evidence (3). For example, in hearts of AMPactivated protein kinase null mice, CDS-2, a rate-limiting enzyme of de novo CL biosynthesis, and ALCAT1 mRNA expression were reduced compared with controls, and this accompanied reduced levels of CL and linoleate in phospholipids within cardiac mitochondria (35). TAZ mRNA expression was unaltered in the hearts of these mice.…”

Section: Discussionmentioning

confidence: 91%

“…It is possible that ALCAT1 may serve as a link between CL remodeling in the ER and mitochondria at these sites. Indeed, ALCAT1 activities and mRNA expression have been shown to be altered in models of apoptosis and diabetes, conditions in which CL metabolism may be altered (35)(36)(37). In addition to the ER ALCAT1, our laboratory previously identified and purified from pig liver mitochondria a 74-kDa protein that could catalyze the acylation of MLCL with fatty acyl-CoAs (20,21).…”

Section: Discussionmentioning

confidence: 99%

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Identification of the Human Mitochondrial Linoleoyl-coenzyme A Monolysocardiolipin Acyltransferase (MLCL AT-1)

Taylor

Hatch

2009

Journal of Biological Chemistry

100

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Here we report the identification of a previously uncharacterized human protein as the human monolysocardiolipin acyltransferase-1 (MLCL AT-1). Pig liver mitochondria were treated with n-butyl alcohol followed by Q-Sepharose chromatography, preparative gel electrophoresis, cytidine diphosphate-1,2-diacyl-sn-glycerol-Sepharose chromatography, and finally monolysocardiolipin-adriamycin-agarose affinity chromatography. Elution with either monolysocardiolipin or linoleoyl coenzyme A revealed a major band at 74 kDa with high specific activity (2,300 pmol/min/mg) for the acylation of monolysocardiolipin to cardiolipin using Cardiolipin (CL)2 is a major phospholipid found in mammalian mitochondria with a multitude of biological functions (reviewed in Refs. 1-7). For example, CL is responsible for modulation of the activity of several mitochondrial enzymes involved in the generation of ATP (reviewed in Refs. 8, 9). In fact, it has been suggested that CL is the "glue" that holds the mitochondrial respiratory complex together (10). The role of CL in genetic diseases such as Barth syndrome, a rare X-linked genetic disorder, is beginning to emerge. Barth syndrome is the only known genetic disease in which the specific biochemical defect is a reduction in CL and accumulation of monolysocardiolipin (MLCL) caused by mutations in the TAZ gene (reviewed in Refs. 2,7,11,12). In addition, the role that CL plays in apoptosis is now well documented (reviewed in Ref. 13). Thus, maintenance of the appropriate content and fatty acyl composition of CL in mitochondria is essential for proper cellular function.The molecular composition of CL appears to be important for the biological function of CL. In general, there is a selection of a particular kind of fatty acid as well as restriction of the number of fatty acid species (14). The major tetra-acyl molecular species found in rat liver (ϳ57% of total) and bovine heart (ϳ48% of total) are 18:2 in each of the four fatty acyl positions of the cardiolipin molecule. Remodeling of CL is essential to obtain this enrichment of CL with linoleate because CL synthase has no molecular species substrate specificity for cytidine-5Ј-diphosphate-1,2-diacyl-sn-glycerol (15). In addition, the species pattern of CL precursors is similar enough to imply that the enzymes of the CL synthetic pathway are not molecular species-selective (16). Alterations in the molecular composition of CL are associated with various disease states, including diabetes and Barth syndrome (17,18

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Identification of the Human Mitochondrial Linoleoyl-coenzyme A Monolysocardiolipin Acyltransferase (MLCL AT-1)

Taylor

Hatch

2009

Journal of Biological Chemistry

100

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“…As HASs are transmembrane proteins, their activity can be phospholipid-dependent (39). Interestingly, AMPK can regulate mitochondrial cardiolipin content (40), and this lipid is known to regulate bacterial HAS (39). As cardiolipin is typically in the mitochondria, this issue could be not critical for eukaryotic HASs, although very recently, it was reported that the AMPK ␥1 subunit can control erythrocyte membrane elasticity (41).…”

Section: Ha Does Not Influence Ampk-mediated Reduction Of Cellmentioning

confidence: 99%

Hyaluronan Synthesis Is Inhibited by Adenosine Monophosphate-activated Protein Kinase through the Regulation of HAS2 Activity in Human Aortic Smooth Muscle Cells

Vigetti

Clerici

Deleonibus

et al. 2011

Journal of Biological Chemistry

106

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Hyaluronan (HA) is an extracellular matrix glycosaminoglycan (GAG) involved in cell motility, proliferation, tissue remodeling, development, differentiation, inflammation, tumor progression, and invasion and controls vessel thickening in cardiovascular diseases. Therefore, the control of HA synthesis could permit the finetuning of cell behavior, but the mechanisms that regulate HA synthesis are largely unknown. Recent studies suggest that the availability of the nucleotide-sugar precursors has a critical role. Because the formation of UDP-sugars is a highly energetically demanding process, we have analyzed whether the energy status of the cell could control GAG production. AMP-activated protein kinase (AMPK) is the main ATP/AMP sensor of mammalian cells, and we mimicked an energy stress by treating human aortic smooth muscle cells (AoSMCs) with the AMPK activators 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside and metformin. Under these conditions, HA synthesis, but not that of the other GAGs, was greatly reduced. We confirmed the inhibitory effect of AMPK using a specific inhibitor and knock-out cell lines. We found that AMPK phosphorylated Thr-110 of human HAS2, which inhibits its enzymatic activity. In contrast, the other two HAS isoenzymes (HAS1 and HAS3) were not modified by the kinase. The reduction of HA decreased the ability of AoSMCs to proliferate, migrate, and recruit immune cells, thereby reducing the pro-atherosclerotic AoSMC phenotype. Interestingly, such effects were not recovered by treatment with exogenous HA, suggesting that AMPK can block the pro-atherosclerotic signals driven by HA by interaction with its receptors.

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“…Slow-twitch muscles have a higher intramuscular TG content as well as more robust expression of enzymes involved in lipid metabolism (4), so it is possible that CEPT1 contributes to the oxidative phenotype by generating PPAR ligands in skeletal muscle. The role of exercise in modulating expression of CEPT1 or related Kennedy pathways enzymes is unknown, but AMPK, an important mediator of the energy depletion associated with exercise, is known to induce the expression of genes encoding enzymes involved in phospholipid biosynthesis (5).…”

Section: Roles Of Specific Lipid Molecules As Ligands For Pparsmentioning

confidence: 99%

Skeletal muscle lipid flux: running water carries no poison

Funai

Semenkovich

2011

American Journal of Physiology-Endocrinology and Metabolism

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Lipids are the most abundant organic constituents in many humans. The rise in obesity prevalence has prompted a need for a more refined understanding of the effects of lipid molecules on cell physiology. In skeletal muscle, deposition of lipids can be associated with insulin resistance that contributes to the development of diabetes. Here, we review the evidence that muscle cells are equipped with the molecular machinery to convert and sequester lipid molecules, thus rendering them harmless. Induction of mitochondrial and lipogenic flux in the setting of elevated lipid deposition can protect muscle from lipid-induced “poisoning” of the cellular machinery. Lipid flux may also be directed toward the synthesis of ligands for nuclear receptors, further enhancing the capacity of muscle for lipid metabolism to promote favorable physiology. Exploiting these mechanisms may have implications for the treatment of obesity-related diseases.

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AMP-Activated Protein Kinase α2 Deficiency Affects Cardiac Cardiolipin Homeostasis and Mitochondrial Function

Cited by 50 publications

References 52 publications

Identification of the Human Mitochondrial Linoleoyl-coenzyme A Monolysocardiolipin Acyltransferase (MLCL AT-1)

Identification of the Human Mitochondrial Linoleoyl-coenzyme A Monolysocardiolipin Acyltransferase (MLCL AT-1)

Hyaluronan Synthesis Is Inhibited by Adenosine Monophosphate-activated Protein Kinase through the Regulation of HAS2 Activity in Human Aortic Smooth Muscle Cells

Skeletal muscle lipid flux: running water carries no poison

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