Deciphering the role of FAM210A in cardiac physiopathology

解读 FAM210A 在心脏病理生理学中的作用

• 批准号: 10717728
• 负责人: Peng Yao
• 金额: $ 48.57万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717728
• 关键词: Adult; Binding; Biochemical; Cardiac; Cardiac Myocytes; Cardiac health; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Data; Disease Progression; EF Hand Motifs; Event; Exhibits; Family; Functional disorder; Genes; Heart; Heart Diseases; Heart failure; Heterozygote; Homeostasis; Human; Hypertrophy; In Vitro; Infection; Integral Membrane Protein; Knockout Mice; Leucine Zippers; Mediating; Membrane Potentials; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Molecular; Morbidity - disease rate; Mus; Mutation; Myoblasts; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardium; Operative Surgical Procedures; Oxidative Phosphorylation; Pathogenicity; Pathologic; Performance; Phenotype; Physiological; Reactive Oxygen Species; Regulation; Ribosomes; Role; Signal Transduction; Stress; Testing; Therapeutic Intervention; United States; antiporter; biological adaptation to stress; blood pump; cardioprotection; comparison control; conditional knockout; heart damage; heart function; improved; in vivo; insight; knock-down; member; mitochondrial cardiomyopathies; mitochondrial dysfunction; mitochondrial membrane; mortality; mouse model; new therapeutic target; non-genetic; novel; overexpression; preventive intervention; protein expression; protein function; respiratory; therapeutic development; transcriptome sequencing

Heart disease is the leading cause of morbidity and mortality worldwide. In healthy myocardium, the mitochondria utilize oxidative phosphorylation to generate ATP and metabolites to support pumping blood throughout the whole body. Given this critical function of mitochondria in the heart, mutations or reductions of essential mitochondrial factors cause mitochondrial cardiomyopathy (MC) in humans and mice. Mitochondrial dysfunction is also a major pathogenic driver in non-genetic ischemic heart disease such as myocardial infarction (MI). Better understanding of mitochondrial protein functions and pathogenic molecular mechanisms underlying mitochondrial dysfunction will promote the development of therapeutics for MC or MI. Recent RNA-seq coupled with ribosome footprint-seq analyses in mouse hearts reveal Fam210a (family with sequence similarity 210 member A) as a hub gene in cardiac remodeling. Our preliminary data suggests reduced FAM210A expression in mouse MI hearts and human ischemic heart failure. Cardiomyocyte (CM)-specific homozygous (Homo) conditional knockout (cKO) of Fam210a in adult mice led to MC and mortality. Interactome analyses reveal that FAM210A binds to mitochondrial Ca2+/H+ exchanger LETM1 (Leucine zipper and EF-hand containing transmembrane protein 1) and promotes mitochondrial Ca2+ (mCa2+) efflux in vitro and in vivo. Therefore, Fam210a deletion in CMs resulted in an elevated mCa2+ and reactive oxygen species and compromised mitochondrial membrane potential. As a result, the mitochondrial respiratory activity was reduced in Fam210a KO CMs, leading to cardiac dysfunction at a late stage. In addition, persistently activated integrated stress response (ISR) contributed to the disease progression in Fam210a cKO hearts. Moreover, CM-specific heterozygous Fam210a cKO mice exhibited lower FAM210A protein expression and more severe cardiac remodeling than control mice under MI. In contrast, AAV9-mediated overexpression of FAM210A could protect hearts from MI-induced cardiac damage and dysfunction. Our central hypothesis is: FAM210A functions as a mitochondrial Ca2+/H+ antiporter regulator and maintains normal mitochondrial and cardiac function. We will test this hypothesis by pursuing 3 aims. Aim 1. Decipher the molecular mechanism of FAM210A in regulating mCa2+ homeostasis. Aim 2. Elucidate the role of FAM210A in regulating cardiac mitochondrial activity and cardiac function. Aim 3. Determine the effects of FAM210A overexpression on the functional performance of mitochondria, CMs, and the heart under MI. Collectively, our studies provide novel insights into the function and mechanisms of FAM210A in regulating cardiac mitochondrial integrity and thus maintaining the normal physiological function of the heart. This project also suggests that reduced FAM210A level contributes to the MI-induced cardiac pathological remodeling and overexpression of FAM210A has a cardioprotective role in MI treatment.

心脏病是全世界发病和死亡的主要原因。在健康的心肌中， 线粒体利用氧化磷酸化产生 ATP 和代谢物来支持泵送 血液遍布全身。鉴于线粒体在心脏中的这一关键功能，突变或 线粒体必需因子的减少会导致人类线粒体心肌病 (MC) 老鼠。线粒体功能障碍也是非遗传性缺血性心脏病的主要致病驱动因素 例如心肌梗塞（MI）。更好地了解线粒体蛋白功能和 线粒体功能障碍的致病分子机制将促进线粒体功能障碍的发生 MC 或 MI 的治疗。最近在小鼠中进行的 RNA 测序与核糖体足迹测序分析相结合 心脏揭示 Fam210a（具有序列相似性的家族 210 成员 A）作为心脏中的枢纽基因 重塑。我们的初步数据表明小鼠 MI 心脏中 FAM210A 表达减少 人类缺血性心力衰竭。心肌细胞 (CM) 特异性纯合 (Homo) 条件敲除 (cKO) 成年小鼠中的 Fam210a 会导致 MC 和死亡。相互作用组分析表明 FAM210A 与线粒体 Ca2+/H+ 交换器 LETM1（亮氨酸拉链和 EF-hand 包含 跨膜蛋白 1) 并促进体外和体内线粒体 Ca2+ (mCa2+) 流出。所以， CM 中 Fam210a 缺失导致 mCa2+ 和活性氧含量升高并受损 线粒体膜电位。结果，线粒体呼吸活性降低 Fam210a KO CM，导致晚期心功能障碍。另外，持续激活 综合应激反应（ISR）导致 Fam210a cKO 心脏的疾病进展。 此外，CM特异性杂合Fam210a cKO小鼠表现出较低的FAM210A蛋白表达 与 MI 下的对照小鼠相比，心脏重塑更为严重。相比之下，AAV9 介导的 FAM210A 的过度表达可以保护心脏免受 MI 引起的心脏损伤和功能障碍。我们的 中心假设是：FAM210A 作为线粒体 Ca2+/H+ 逆向转运蛋白调节剂发挥作用并维持 线粒体和心脏功能正常。我们将通过追求 3 个目标来检验这个假设。目标1。 解读 FAM210A 调节 mCa2+ 稳态的分子机制。目标 2. 阐明 FAM210A 在调节心脏线粒体活性和心脏功能中的作用。目标 3. 确定 FAM210A 过表达对线粒体、CM 和心脏功能的影响 在军事情报下。总的来说，我们的研究为 FAM210A 的功能和机制提供了新的见解 调节心脏线粒体的完整性，从而维持线粒体的正常生理功能 心。该项目还表明，FAM210A 水平降低有助于 MI 诱发的心脏疾病 FAM210A 的病理重塑和过度表达在 MI 治疗中具有心脏保护作用。