Department of Cardiology, PLA General Hospital, Beijing, China.
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA.
Basic Res Cardiol. 2018 May 9;113(4):23. doi: 10.1007/s00395-018-0682-1.
Mitochondrial fission and mitophagy are considered key processes involved in the pathogenesis of cardiac microvascular ischemia reperfusion (IR) injury although the upstream regulatory mechanism for fission and mitophagy still remains unclear. Herein, we reported that NR4A1 was significantly upregulated following cardiac microvascular IR injury, and its level was positively correlated with microvascular collapse, endothelial cellular apoptosis and mitochondrial damage. However, NR4A1-knockout mice exhibited resistance against the acute microvascular injury and mitochondrial dysfunction compared with the wild-type mice. Functional studies illustrated that IR injury increased NR4A1 expression, which activated serine/threonine kinase casein kinase2 α (CK2α). CK2α promoted phosphorylation of mitochondrial fission factor (Mff) and FUN14 domain-containing 1 (FUNDC1). Phosphorylated activation of Mff enhanced the cytoplasmic translocation of Drp1 to the mitochondria, leading to fatal mitochondrial fission. Excessive fission disrupted mitochondrial function and structure, ultimately triggering mitochondrial apoptosis. In addition, phosphorylated inactivation of FUNDC1 failed to launch the protective mitophagy process, resulting in the accumulation of damaged mitochondria and endothelial apoptosis. By facilitating Mff-mediated mitochondrial fission and FUNDC1-required mitophagy, NR4A1 disturbed mitochondrial homeostasis, enhanced endothelial apoptosis and provoked microvascular dysfunction. In summary, our data illustrated that NR4A1 serves as a novel culprit factor in cardiac microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy. Novel therapeutic strategies targeting the balance among NR4A1, fission and mitophagy might provide survival advantage to microvasculature following IR stress.
线粒体裂变和线粒体自噬被认为是心脏微血管缺血再灌注 (IR) 损伤发病机制中的关键过程，尽管裂变和线粒体自噬的上游调节机制仍不清楚。在此，我们报道 NR4A1 在心脏微血管 IR 损伤后显著上调，其水平与微血管塌陷、内皮细胞凋亡和线粒体损伤呈正相关。然而，与野生型小鼠相比，NR4A1 敲除小鼠对急性微血管损伤和线粒体功能障碍表现出抗性。功能研究表明，IR 损伤增加了 NR4A1 的表达，从而激活了丝氨酸/苏氨酸激酶酪蛋白激酶 2α (CK2α)。CK2α 促进线粒体裂变因子 (Mff) 和 FUN14 结构域包含蛋白 1 (FUNDC1) 的丝氨酸/苏氨酸磷酸化。磷酸化激活的 Mff 增强了 Drp1 向线粒体的细胞质易位，导致致命的线粒体裂变。过度裂变破坏了线粒体的功能和结构，最终引发线粒体凋亡。此外，磷酸化失活的 FUNDC1 无法启动保护性自噬过程，导致受损线粒体和内皮细胞凋亡的积累。通过促进 Mff 介导的线粒体裂变和 FUNDC1 所需的自噬，NR4A1 扰乱了线粒体的动态平衡，增强了内皮细胞凋亡，并引发了微血管功能障碍。总之，我们的数据表明，NR4A1 是心脏微血管 IR 损伤的一个新的罪魁祸首，它通过同步提高裂变和抑制自噬来发挥作用。针对 NR4A1、裂变和自噬之间平衡的新治疗策略可能为 IR 应激后的微血管提供生存优势。
