Abstract
Cardiolipin is a class of mitochondrial specific phospholipid, which is intricately involved in mitochondrial functionality. Differences in cardiolipin species exist in a variety of tissues and diseases. It has been demonstrated that the cardiolipin profile is a key modulator of the functions of many mitochondrial proteins. However, the chemical mechanism(s) leading to normal and/or pathological distribution of cardiolipin species remain elusive. Herein, we describe a novel approach for investigating the molecular mechanism of cardiolipin remodeling through a dynamic simulation. This approach applied data from shotgun lipidomic analyses of the heart, liver, brain, and lung mitochondrial lipidomes to model cardiolipin remodeling, including relative content, regiospecificity, and isomeric composition of cardiolipin species. Generated cardiolipin profiles were nearly identical to those determined by shotgun lipidomics. Importantly, the simulated isomeric compositions of cardiolipin species were further substantiated through product ion analysis. Finally, unique enzymatic activities involved in cardiolipin remodeling were assessed from the parameters used in the dynamic simulation of cardiolipin profiles. Collectively, we described, verified, and demonstrated a novel approach by integrating both lipidomic analysis and dynamic simulation to study cardiolipin biology. We believe this study provides a foundation to investigate cardiolipin metabolism and bioenergetic homeostasis in normal and disease states.
Highlights
Cardiolipin is a class of mitochondrial specific phospholipid, which is intricately involved in mitochondrial functionality
Analysis of cardiolipin molecular species and their acyl chain regioisomers in myocardial, hepatic, lung, and brain mitochondria revealed a diverse distribution that provided insight into the biochemical processes that mediated the distinct distributions of cardiolipins in these tissues
Based on the premise that the diversity of cardiolipin molecular species in various organs was dependent on the availability of different acyl chains in position of choline glycerophospholipids (PC) and PE as well as the acyl CoA composition and the acyl selectivities of the involved acyltransferases and transacylases, a dynamic model was constructed to identify the critical reactions necessary for the generation of mature cardiolipins
Summary
Cardiolipin is a class of mitochondrial specific phospholipid, which is intricately involved in mitochondrial functionality. We describe a novel approach for investigating the molecular mechanism of cardiolipin remodeling through a dynamic simulation. This approach applied data from shotgun lipidomic analyses of the heart, liver, brain, and lung mitochondrial lipidomes to model cardiolipin remodeling, including relative content, regiospecificity, and isomeric composition of cardiolipin species. The simulated isomeric compositions of cardiolipin species were further substantiated through product ion analysis. Unique enzymatic activities involved in cardiolipin remodeling were assessed from the parameters used in the dynamic simulation of cardiolipin profiles. We described, verified, and demonstrated a novel approach by integrating both lipidomic analysis and dynamic simulation to study cardiolipin biology. Han. Dynamic simulation of cardiolipin remodeling: greasing the wheels for an interpretative approach to lipidomics.
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