State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School of Nanjing University, Nanjing 210093, China.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
Development. 2021 Apr 15;148(8). doi: 10.1242/dev.199026. Epub 2021 Apr 16.
Mammalian heart development relies on cardiomyocyte mitochondrial maturation and metabolism. Embryonic cardiomyocytes make a metabolic shift from anaerobic glycolysis to oxidative metabolism by mid-gestation. VHL-HIF signaling favors anaerobic glycolysis but this process subsides by E14.5. Meanwhile, oxidative metabolism becomes activated but its regulation is largely elusive. Here, we first pinpointed a crucial temporal window for mitochondrial maturation and metabolic shift, and uncovered the pivotal role of the SRCAP chromatin remodeling complex in these processes in mouse. Disruption of this complex massively suppressed the transcription of key genes required for the tricarboxylic acid cycle, fatty acid β-oxidation and ubiquinone biosynthesis, and destroyed respirasome stability. Furthermore, we found that the SRCAP complex functioned through H2A.Z deposition to activate transcription of metabolic genes. These findings have unveiled the important physiological functions of the SRCAP complex in regulating mitochondrial maturation and promoting oxidative metabolism during heart development, and shed new light on the transcriptional regulation of ubiquinone biosynthesis.
哺乳动物心脏发育依赖于心肌细胞线粒体的成熟和代谢。胚胎心肌细胞在妊娠中期从无氧糖酵解向氧化代谢转变。VHL-HIF 信号通路有利于无氧糖酵解，但这一过程在 E14.5 时就减弱了。与此同时，氧化代谢开始活跃，但它的调节在很大程度上还不清楚。在这里，我们首先确定了线粒体成熟和代谢转变的关键时间窗口，并揭示了 SRCAP 染色质重塑复合物在这些过程中的关键作用。该复合物的破坏极大地抑制了三羧酸循环、脂肪酸β-氧化和泛醌生物合成所需的关键基因的转录，并破坏了呼吸体的稳定性。此外，我们发现 SRCAP 复合物通过 H2A.Z 的沉积来激活代谢基因的转录。这些发现揭示了 SRCAP 复合物在调节心脏发育过程中线粒体成熟和促进氧化代谢方面的重要生理功能，并为泛醌生物合成的转录调控提供了新的视角。
