Lipidome Atlas of the Developing Heart Uncovers Dynamic Membrane Lipid Attributes Underlying Cardiac Structural and Metabolic Maturation

• Published in: Research (Washington) 2022, Vol.2022, p.0006
• Main Authors: Miao, Huan, Li, Bowen, Wang, Zehua, Mu, Jinming, Tian, Yanlin, Jiang, Binhua, Zhang, Shaohua, Gong, Xia, Shui, Guanghou, Lam, Sin Man
• Format: Article
• Language: English
• ISSN: 2639-5274; 2639-5274
• DOI: 10.34133/research.0006

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 development 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 , and 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.