Département de Médecine - Service de Cardiologie, Faculté de Médecine et des Sciences de la Santé, Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC, Canada.
Département de microbiologie et d'infectiologie, Faculté de Médecine et des Sciences de la Santé, Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC, Canada.
FASEB J. 2021 May;35(5):e21544. doi: 10.1096/fj.202002293RR.
Serine-rich splicing factor 3 (SRSF3) was recently reported as being necessary to preserve RNA stability via an mTOR mechanism in a cardiac mouse model in adulthood. Here, we demonstrate the link between Srsf3 and mitochondrial integrity in an embryonic cardiomyocyte-specific Srsf3 conditional knockout (cKO) mouse model. Fifteen-day-old Srsf3 cKO mice showed dramatically reduced (below 50%) survival and reduced the left ventricular systolic performance, and histological analysis of these hearts revealed a significant increase in cardiomyocyte size, confirming the severe remodeling induced by Srsf3 deletion. RNA-seq analysis of the hearts of 5-day-old Srsf3 cKO mice revealed early changes in expression levels and alternative splicing of several transcripts related to mitochondrial integrity and oxidative phosphorylation. Likewise, the levels of several protein complexes of the electron transport chain decreased, and mitochondrial complex I-driven respiration of permeabilized cardiac muscle fibers from the left ventricle was impaired. Furthermore, transmission electron microscopy analysis showed disordered mitochondrial length and cristae structure. Together with its indispensable role in the physiological maintenance of mouse hearts, these results highlight the previously unrecognized function of Srsf3 in regulating the mitochondrial integrity.
丝氨酸丰富的剪接因子 3（SRSF3）最近被报道在成年小鼠心脏模型中通过 mTOR 机制对 RNA 稳定性起必需作用。在这里，我们在胚胎心肌细胞特异性 Srsf3 条件性敲除（cKO）小鼠模型中证明了 Srsf3 与线粒体完整性之间的联系。15 天大的 Srsf3 cKO 小鼠表现出明显降低的（低于 50%）存活率和左心室收缩性能降低，这些心脏的组织学分析显示心肌细胞大小显著增加，证实了 Srsf3 缺失引起的严重重构。5 天大的 Srsf3 cKO 小鼠心脏的 RNA-seq 分析显示，与线粒体完整性和氧化磷酸化相关的几个转录本的表达水平和可变剪接发生早期变化。同样，几个电子传递链蛋白复合物的水平降低，并且来自左心室的心肌纤维的线粒体复合物 I 驱动的呼吸作用受损。此外，透射电子显微镜分析显示线粒体长度和嵴结构紊乱。结合其在小鼠心脏生理维持中的不可或缺作用，这些结果突出了 Srsf3 在调节线粒体完整性方面的先前未被认识到的功能。
