Lipidome Atlas of the Developing Heart Uncovers Dynamic Membrane Lipid Attributes Underlying Cardiac Structural and Metabolic Maturation (vol 2022, 0006, 2022)

Precise metabolic rewiring during heart organogenesis underlies normal cardiac development. Herein, we utilized high-coverage, quantitative lipidomic approaches to construct lipidomic atlases of whole hearts (861 lipids; 31 classes) and mitochondria (587 lipids; 27 classes) across prenatal and postnatal developmental stages in mice. We uncovered the progressive formation of docosahexaenoyl-phospholipids and enhanced remodeling of C18:2, C20:3, and C20:4 fatty acyl moieties into cardiolipins as cardiac de-velopment progresses. A preferential flow of ceramides toward sphingomyelin biosynthesis over complex glycosphingolipid formation was also noted. Using maSigPro and GPclust algorithms, we identified a repertoire of 448 developmentally dynamic lipids and mapped their expression patterns to a library of 550 biologically relevant developmentally dynamic genes. Our combinatorial transcriptomics and lipidomics approaches identified Hadha, Lclat1, and Lpcat3 as candidate molecular drivers governing the dynamic remodeling of cardiolipins and phospholipids, respectively, in heart development. Our analyses revealed that postnatal cardiolipin remodeling in the heart constitutes a biphasic process, which first accumulates polyunsaturated C78-cardiolipins prior to tetralinoleoyl cardiolipin forming the predominant species. Multiomics analyses supplemented with transmission electron microscopy imaging uncovered enhanced mitochondria???lipid droplet contacts mediated by perilipin-5. Our combinatorial analyses of multiomics data uncovered an association between mitochondrial-resident, docosahexaenoic acid-phospholipids and messenger RNA levels of proton-transporting adenosine triphosphate synthases on inner mitochondrial membranes, which adds credence to the membrane pacemaker theory of metabolism. The current findings offer lipid-centric biological insights potentially important to understanding the molecular basis of cardiac metabolic flexibility and disease pathology.