Kiebish 2012 J Biol Chem

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Kiebish MA, Yang K, Sims HF, Jenkins CM, Liu X, Mancuso DJ, Zhao Z, Guan S, Abendschein DR, Han X, Gross RW (2012) Myocardial regulation of lipidomic flux by cardiolipin synthase: Setting the beat for bioenergetic efficiency. J Biol Chem 287:25086-97.

» PMID: 22584571 Open Access

Kiebish MA, Yang K, Sims HF, Jenkins CM, Liu X, Mancuso DJ, Zhao Z, Guan S, Abendschein DR, Han X, Gross RW (2012) J Biol Chem

Abstract: Lipidomic regulation of mitochondrial cardiolipin content and molecular species composition is a prominent regulator of bioenergetic efficiency. However, the mechanisms controlling cardiolipin metabolism during health or disease progression have remained elusive. Herein, we demonstrate that cardiac myocyte-specific transgenic expression of cardiolipin synthase results in accelerated cardiolipin lipidomic flux that impacts multiple aspects of mitochondrial bioenergetics and signaling. During the postnatal period, cardiolipin synthase transgene expression results in marked changes in the temporal course of maturation of cardiolipin molecular species during development. In adult myocardium, cardiolipin synthase transgene expression leads to a marked increase in symmetric tetra18:2 molecular species without a change in total cardiolipin content. Mechanistically, these alterations result from increased cardiolipin remodeling by sequential phospholipase and transacylase/acyltransferase activities in conjunction with a decrease in phosphatidylglycerol content. Moreover, cardiolipin synthase transgene expression results in alterations in signaling metabolites including a marked increase in the cardioprotective eicosanoid 14,15 EET. Examination of mitochondrial bioenergetic function by high resolution respirometry demonstrated that cardiolipin synthase transgene expression resulted in improved mitochondrial bioenergetic efficiency demonstrated by enhanced electron transport chain coupling using multiple substrates as well as by salutary changes in Complex III and IV activities. Furthermore, transgenic expression of cardiolipin synthase attenuated maladaptive cardiolipin remodeling and bioenergetic inefficiency in myocardium rendered diabetic by streptozotocin treatment. Collectively, these results demonstrate the unanticipated role of cardiolipin synthase in maintaining physiologic membrane structure and function even under metabolic stress thereby identifying cardiolipin synthase as a novel therapeutic target to attenuate mitochondrial dysfunction in diabetic cardiomyopathy.

Keywords: Cardiolipin synthase

O2k-Network Lab: US MO St Louis Gross RW


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Organism: Mouse  Tissue;cell: Heart  Preparation: Homogenate 


Pathway: N, S, CIV, NS  HRR: Oxygraph-2k