Shotgun Lipidomics Reveals the Temporally Dependent, Highly Diversified Cardiolipin Profile in the Mammalian Brain: Temporally Coordinated Postnatal Diversification of Cardiolipin Molecular Species with Neuronal Remodeling

Abstract

Large-scale neuronal remodeling through apoptosis occurs shortly after birth in all known mammalian species. Apoptosis, in large part, depends upon critical interactions between mitochondrial membranes and cytochrome c. Herein, we examined the hypothesis that the largescale reorganization of neuronal circuitry after birth is accompanied by profound alterations in cardiolipin (CL) content and molecular species distribution. During embryonic development, over 100 CL molecular species were identified and quantitated in murine neuronal tissues. The embryonic CL profile was notable for the presence of abundant amounts of relatively short aliphatic chains (e.g., palmitoleic and oleic acids). In sharp contrast, after birth, the CL profile contained a remarkably complex repertoire of CL molecular species, in which the signaling fatty acids (i.e., arachidonic and docosahexaenoic acids) were markedly increased. These results identify the rapid remodeling of CL in the perinatal period with resultant alterations in the physical properties of the mitochondrial membrane. The complex distribution of aliphatic chains in the neuronal CL pool is separate and distinct from that in other organs (e.g., heart, liver, etc.), where CL molecular species contain predominantly only one major type of aliphatic chain (e.g., linoleic acid). Analyses of mRNA levels by real-time quantitative polymerase chain reactions suggested that the alterations in CL content were due to the combined effects of both attenuation of de novo CL biosynthesis and decreased remodeling of CL. Collectively, these results provide a new perspective on the complexity of CL in neuronal signaling, mitochondrial bioenergetics, and apoptosis.Cardiolipin (1,3-diphosphatidyl-sn-glycerol, CL) 1 is exclusively present in the mitochondrial membrane of eukaryotic cells (1), whose evolutionary origins can be traced back to bacterial membranes. Each CL molecular species is uniquely comprised of a dimer of two phosphatidyl † This work was supported by NIA Grants R01 AG23168 and R01 AG31675, NIH Grant P01 HL57278, and the Neurosciences Education and Research Foundation.* To whom correspondence should be addressed: Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Internal Medicine, Washington University School of Medicine, Box 8020, 660 South Euclid Avenue, St. Louis, MO 63110. Telephone: (314) 362−2690. Fax: (314) 362−1402. E-mail: xianlin@wustl.edu.. Publisher's Disclaimer: This PDF receipt will only be used as the basis for generating PubMed Central (PMC) documents. PMC documents will be made available for review after conversion (approx. 2−3 weeks time). Any corrections that need to be made will be done at that time. No materials will be released to PMC without the approval of an author. Only the PMC documents will appear on PubMed Central --this PDF Receipt will not appear on PubMed Central. 1 Abbreviation: CL, cardiolipin; FA, fatty acid or fatty acyl; FACO, fatty acyl-CoA oxidase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HPLC, high-pe...

Dynamic simulation of cardiolipin remodeling: greasing the wheels for an interpretative approach to lipidomics

“…3B ). For example, a similar broad distribution of cardiolipin molecular species was observed between day 5 and 15 for normal mouse cardiac development (data not shown) as well as in mature mouse brain ( 16,26 ). It is interesting that this broad distribution of cardiolipin molecular species is also observed in various disease states, culture conditions, and transgenic models of enzymes that catalyze cardiolipin remodeling ( 23,(41)(42)(43)(44)(45).…”

“…Although that approach demonstrated novel insight into potential mechanisms governing acyl selectivity, it did not directly address the importance of kinetics in the generation of cardiolipin acyl chain distributions. In addition, that approach only addressed distributions that are relegated by tetralinoleic abundance of cardiolipin; however, brain cardiolipin does not conform to that model ( 16,26 ). Moreover, alterations in free energies are complex functions of enthalpy and entropy driven by altering molecular membrane symmetry and the order/disorder at the membrane interface.…”

“…The pellet was resuspended in HM buffer without BSA, and the protein concentration of the resuspended mitochondrial fractions was determined using the BCA protein assay (Thermo Scientifi c, Rockford, IL). disease states ( 12,13,(15)(16)(17)(18)(19). This diversity is regulated by differences in cardiolipin biosynthesis and catabolism, remodeling acyl selectivities, and transacylase as well as acyltransferase activities ( 20,21 ).…”

“…This is likely because the organs generally maintain their cardiolipin pattern after development, although cardiolipin remodeling continues during aging with only subtle changes to the acyl chain composition or distribution ( 16,(46)(47)(48).…”

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

“…Decreases in cardiolipin content and alterations in molecular species composition have previously been demonstrated in aging as well as multiple pathologic disorders (48 -50). Newly synthesized cardiolipin typically undergoes remodeling to incorporate longer and more highly unsaturated acyl chains (51). Under normal conditions, CL remodeling typically is initiated by the action of a phospholipase to generate lyso-CL that is subsequently re-acylated by either transacylation or acylCoA-mediated acyltransferase activity (52).…”