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

Mancuso, David J.; Kotzbauer, Paul T.; Wozniak, David F.; Sims, Harold F.; Jenkins, Christopher M.; Guan, Shaoping; Han, Xianlin; Yang, Kui; Sun, Guorong; Malik, Ibrahim; Conyers, Sara; Green, Karen G.; Schmidt, Robert E.; Gross, Richard W.

doi:10.1074/jbc.m109.055194

Cited by 101 publications

(95 citation statements)

References 79 publications

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“…Genetic ablation of iPLA 2 ␥ resulted in the generation of viable progeny that demonstrated decreased growth, cold intolerance due to impaired fat burning in brown adipose tissue, and defects in ascorbate-stimulated mitochondrial Complex IV function in the myocardium ( 18 ). Furthermore, these knockout mice also showed alterations in hippocampal CL content, mitochondrial degeneration, and cognitive dysfunction ( 19 ). These reports suggest that iPLA 2 ␥ , a mitochondrial iPLA 2 , regulates mitochondrial inner membrane lipid metabolism, perturbation of which may profoundly infl uence fatty acid ␤ -oxidation, oxygen consumption, energy expenditure, and thus, tissue homeostasis.…”

Section: Methodsmentioning

confidence: 99%

“…Recent gene-targeting studies of iPLA 2 ␥ have unveiled a particular role of this enzyme in the metabolism of cardiolipin (CL), a critical mitochondrial phospholipid that facilitates protein supercomplex formation in the mitochondrial inner membrane, thereby allowing optimal electron transport chain function ( 18,19 ). Genetic ablation of iPLA 2 ␥ resulted in the generation of viable progeny that demonstrated decreased growth, cold intolerance due to impaired fat burning in brown adipose tissue, and defects in ascorbate-stimulated mitochondrial Complex IV function in the myocardium ( 18 ).…”

Section: Methodsmentioning

confidence: 99%

“…In this study, we established an additional line of iPLA 2 ␥ -defi cient mice and found that the mice showed growth retardation and reduced exercise capacity, which had also been demonstrated for the initial line of null mice ( 18,19 ). We found that this phenotype was caused by skeletal muscle atrophy.…”

mentioning

confidence: 95%

“…In the previous studies, the content of CL, a phospholipid that is mostly confi ned to mitochondrial membranes, was changed in the heart and brain of iPLA 2 ␥ -defi cient mice ( 18,19 ). We also investigated the phospholipid composition in the skeletal muscle from iPLA 2 ␥ -KO mice compared with that from WT mice.…”

Section: Alterations Of Phospholipid Compositions In Skeletal Muscle mentioning

confidence: 99%

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Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of Group VIB Ca2+-independent phospholipase A2γ-deficient mice

Yoda

Hachisu

Taketomi

et al. 2010

Journal of Lipid Research

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Supplementary key words cardiolipin • mitochondria • muscle • phospholipidsPhospholipase A 2 (PLA 2 ) enzymes catalyze the cleavage of the sn -2 ester bond of glycerophospholipids to yield free fatty acids and lysophospholipids, thereby playing critical roles in cellular lipid metabolisms linked to energy storage, membrane remodeling, and lipid mediator signaling. In the membrane remodeling reaction, fatty acyl groups are fi rst removed (deacylated) by PLA 2 and then replaced (reacylated) with different fatty acyl groups by acyltransferases, which allow membrane phospholipids to acquire a variation of molecular species. In the signaling reaction, polyunsaturated fatty acids [typically arachidonic acid (AA)] and lysophospholipids released by the action of PLA 2 s are metabolized to various lipid mediators, such as prostaglandins (PG), leukotrienes, and platelet-activating factor, which exert a variety of biological actions through their cognate receptors. Abstract Group VIB Ca2+ -independent phospholipase A 2 ␥ (iPLA 2 ␥ ) is a membrane-bound iPLA 2 enzyme with unique features, such as the utilization of distinct translation initiation sites and the presence of mitochondrial and peroxisomal localization signals. Here we investigated the physiological functions of iPLA 2 ␥ by disrupting its gene in mice. iPLA 2 ␥ -knockout (KO) mice were born with an expected Mendelian ratio and appeared normal and healthy at the age of one month but began to show growth retardation from the age of two months as well as kyphosis and significant muscle weakness at the age of four months. Electron microscopy revealed swelling and reduced numbers of mitochondria and atrophy of myofi laments in iPLA 2 ␥ -KO skeletal muscles. Increased lipid peroxidation and the induction of several oxidative stress-related genes were also found in the iPLA 2 ␥ -KO muscles. These results provide evidence that impairment of iPLA 2 ␥ causes mitochondrial dysfunction and increased oxidative stress, leading to the loss of skeletal muscle structure and function. We further found that the compositions of cardiolipin and other phospholipid subclasses were altered and that the levels of myoprotective prostanoids were reduced in iPLA 2 ␥ -KO skeletal muscle. Thus, in addition to maintenance of homeostasis of the mitochondrial membrane, iPLA 2 ␥ may contribute to modulation of lipid mediator production in vivo. -Yoda, E., K. Hachisu, Y. Taketomi, K. Yoshida, M. Nakamura, K. Ikeda, R. Taguchi, Y. Nakatani, H. Kuwata, M. Murakami, I. Kudo, and S. Hara. Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of Group VIB Ca 2+ -independent phospholipase A2 ␥ -defi cient mice. J. Lipid Res.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 95%

Section: Alterations Of Phospholipid Compositions In Skeletal Muscle mentioning

confidence: 99%

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Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of Group VIB Ca2+-independent phospholipase A2γ-deficient mice

Yoda

Hachisu

Taketomi

et al. 2010

Journal of Lipid Research

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“…The enzyme demonstrated high lipase activity in sn-2-radiolabeled phosphatidylcholine (PC) and plasmenylcholine (PE) in Sf9 cells (Mancuso et al, 2000). Loss function of calcium-independent phospholipase A 2 γ in mice showed several symptoms in hippocampal phospholipid change, cognitive dysfunction and bioenergetic dysfunction including abnormal CL content with elevated short acyl chain species, enlarged and degenerated mitochondria and reduced ascorbate-induced Complex IV-mediated oxygen consumption (Mancuso et al, 2009;Mancuso et al, 2007). In Drosophila, iPLA2-VIA, or calcium-independent phospholipase A2 group VIA suppressed the phenotype of male sterility in tafazzin mutant fly; and it also prevents cardiolipin depletion/monolysocardiolipin accumulation in this mutant; however, loss function of iPLA2-VIA did not affect the content of cardiolipin profile in wild type individuals.…”

Section: Calcium-independent Phospholipase A2 (Ipla2)mentioning

confidence: 99%

The Role of Cardiolipin Remodeling in Mitochondrial Function and Human Diseases

Yan

Kang²

2011

JMBR

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Cardiolipin (CL), one of bisphosphatidyl glycerol lipid, is found to contain high level of C18:2 acyl chains and exist exclusively in inner membranes of mitochondria. Cardiolipin remodeling is the process for CL to attain its specific acyl chains. With the purpose of introducing this interesting field to readers, in this review, we elucidate the role of cardiolipin in normal functions of mitochondria by analyzing the physical and chemical characters of cardiolipin; we introduce the current models of cardiolipin remodeling by analyzing the enzymes involved in this process; we reviewed the latest progress in the clinical implications of cardiolipin remodeling.

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