Striated preferentially expressed gene deficiency leads to mitochondrial dysfunction in developing cardiomyocytes

作者全名："Li, Gu; Huang, He; Wu, Yanshuang; Shu, Chang; Hwang, Narae; Li, Qifei; Zhao, Rose; Lam, Hilaire C.; Oldham, William M.; EI-Chemaly, Souheil; Agrawal, Pankaj B.; Tian, Jie; Liu, Xiaoli; Perrella, Mark A."

作者地址："[Li, Gu; Wu, Yanshuang; Liu, Xiaoli; Perrella, Mark A.] Brigham & Womens Hosp, Dept Pediat, Div Newborn Med, Boston, MA 02115 USA; [Li, Gu; Shu, Chang; Tian, Jie] Chongqing Med Univ, Dept Cardiol, Chongqing 400015, Peoples R China; [Li, Gu; Shu, Chang; Tian, Jie] Chongqing Med Univ, Childrens Hosp, Dept Pulm, Chongqing 400015, Peoples R China; [Huang, He] Chongqing Med Univ, Affiliated Hosp 2, Dept Anesthesiol, Chongqing 400010, Peoples R China; [Li, Qifei; Agrawal, Pankaj B.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Genet & Genom, Boston, MA 02115 USA; [Li, Qifei; Agrawal, Pankaj B.] Univ Miami, Dept Pediat & Jackson Hlth Syst, Miller Sch Med, Div Neonatol, Miami, FL 33136 USA; [Huang, He; Wu, Yanshuang; Shu, Chang; Hwang, Narae; Zhao, Rose; Lam, Hilaire C.; Oldham, William M.; EI-Chemaly, Souheil; Liu, Xiaoli; Perrella, Mark A.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA"

通信作者："Liu, XL (通讯作者)，Brigham & Womens Hosp, Dept Pediat, Div Newborn Med, Boston, MA 02115 USA.; Liu, XL (通讯作者)，Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA."

来源：BASIC RESEARCH IN CARDIOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001156092300006

JCR分区：Q1

影响因子：9.5

年份：2024

卷号：119

期号：1

开始页：151

结束页：168

文献类型：Article

关键词：Speg; Dilated cardiomyopathy; Mitochondria; PGC-1 alpha phosphorylation

摘要："A deficiency of striated preferentially expressed gene (Speg), a member of the myosin light chain kinase family, results in abnormal myofibril structure and function of immature cardiomyocytes (CMs), corresponding with a dilated cardiomyopathy, heart failure and perinatal death. Mitochondrial development plays a role in cardiomyocyte maturation. Therefore, this study investigated whether Speg deficiency ( - / - ) in CMs would result in mitochondrial abnormalities. Speg wild-type and Speg(-/-) C57BL/6 littermate mice were utilized for assessment of mitochondrial structure by transmission electron and confocal microscopies. Speg was expressed in the first and second heart fields at embryonic (E) day 7.5, prior to the expression of mitochondrial Na+/Ca2+/Li+ exchanger (NCLX) at E8.5. Decreases in NCLX expression (E11.5) and the mitochondrial-to-nuclear DNA ratio (E13.5) were observed in Speg(-/-) hearts. Imaging of E18.5 Speg(-/-) hearts revealed abnormal mitochondrial cristae, corresponding with decreased ATP production in cells fed glucose or palmitate, increased levels of mitochondrial superoxide and depolarization of mitochondrial membrane potential. Interestingly, phosphorylated (p) PGC-1 alpha, a key mediator of mitochondrial development, was significantly reduced in Speg(-/- )hearts during screening for targeted genes. Besides Z-line expression, Speg partially co-localized with PGC-1 alpha in the sarcomeric region and was found in the same complex by co-immunoprecipitation. Overexpression of a Speg internal serine/threonine kinase domain in Speg(-/-) CMs promoted translocation of pPGC-1 alpha into the nucleus, and restored ATP production that was abolished by siRNA-mediated silencing of PGC-1 alpha. Our results demonstrate a critical role of Speg in mitochondrial development and energy metabolism in CMs, mediated in part by phosphorylation of PGC-1 alpha."

基金机构：American Heart Association

基金资助正文："The authors thank Bonna Ith for his assistance with tissue processing, embedding, and sectioning for immunostaining analyses. We thank Dr. Jewel Imani and Dr. Shikshya Shrestha for technical assistance."