Miao Huan, Li Bowen, Wang Zehua, Mu Jinming, Tian Yanlin, Jiang Binhua, Zhang Shaohua, Gong Xia, Shui Guanghou, Lam Sin Man
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Research (Wash D C). 2022 Dec 19;2022:0006. doi: 10.34133/research.0006. eCollection 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 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.
心脏器官发生过程中精确的代谢重排是正常心脏发育的基础。在此，我们利用高覆盖度、定量脂质组学方法构建了小鼠产前和产后发育阶段全心脏（861种脂质；31类）和线粒体（587种脂质；27类）的脂质组图谱。我们发现，随着心脏发育的进行，二十二碳六烯酰磷脂逐渐形成，C18:2、C20:3和C20:4脂肪酸酰基部分向心磷脂的重塑增强。还注意到神经酰胺优先流向鞘磷脂生物合成而非复合糖鞘脂形成。使用maSigPro和GPclust算法，我们鉴定出448种发育动态脂质，并将它们的表达模式映射到550个生物学相关的发育动态基因库中。我们的转录组学和脂质组学联合方法分别鉴定出 和 作为心脏发育中心磷脂和磷脂动态重塑的候选分子驱动因素。我们的分析表明，心脏出生后的心磷脂重塑是一个双相过程，首先积累多不饱和C78-心磷脂，然后四亚油酰心磷脂形成主要种类。多组学分析辅以透射电子显微镜成像揭示了由 perilipin-5介导的线粒体-脂滴接触增强。我们对多组学数据的联合分析揭示了线粒体内驻留的二十二碳六烯酸磷脂与线粒体内膜上质子转运三磷酸腺苷合酶的信使RNA水平之间的关联，这为代谢的膜起搏器理论提供了可信度。目前的研究结果提供了以脂质为中心的生物学见解，可能对理解心脏代谢灵活性和疾病病理学的分子基础很重要。
