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Journal of Lipid Research, Vol. 47, 864-879, April 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Methods

Shotgun lipidomics of cardiolipin molecular species in lipid extracts of biological samples

Xianlin Han^1,*,, Kui Yang^*, Jingyue Yang^*, Hua Cheng^* and Richard W. Gross^*,,,**

^* Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, St. Louis, MO 63110
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110
^** Department of Chemistry, Washington University, St. Louis, MO 63130

Published, JLR Papers in Press, January 31, 2006.

¹ To whom correspondence should be addressed. e-mail: xianlin{at}wustl.edu

Cardiolipin is a prominent component of the mitochondrial inner membranes contributing to the regulation of multiple discrete mitochondrial functions. Here, we extend shotgun lipidomics to identify and quantitate cardiolipin molecular species directly from lipid extracts of biological samples. Three shotgun lipidomics approaches for analyses of cardiolipin molecular species were developed using either a continuous ion-transmission instrument (i.e., triple-quadrupole type) with either low or high mass resolution settings or a high mass resolution hybrid pulsed instrument [i.e., quadrupole time-of-flight (QqTOF) type]. Three chemical principles were used for the development of these approaches. These include the marked enrichment of linoleate in cardiolipin to maximize the signal-to-noise ratio, the specific neutral loss of ketenes from doubly charged cardiolipin molecular ions to yield doubly charged triacyl monolysocardiolipins, and the doubly charged character of two phosphates in each cardiolipin molecular species. Through these techniques, we identified and quantified the specific molecular species profiles of cardiolipin directly from lipid extracts of mouse heart, liver, and skeletal muscle. The accuracy (5%) and the low end of the linear dynamic range (10 fmol/µl) for quantitation make these approaches useful for studying alterations in cardiolipin metabolism in multiple disease states using either type of mass spectrometer.

Supplementary key words electrospray ionization mass spectrometry • mitochondria • multidimensional mass spectrometry

Abbreviations: ESI, electrospray ionization; m:n, acyl chain containing m carbons and n double bonds; QqQ, triple-quadrupole; T14:0 CL, tetramyristoyl cardiolipin

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