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Open Access 26-12-2023 | Cardiomyopathy | Original Contribution

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

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

Published in: Basic Research in Cardiology | Issue 1/2024

Abstract

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-1α, 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-1α 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-1α into the nucleus, and restored ATP production that was abolished by siRNA-mediated silencing of PGC-1α. Our results demonstrate a critical role of Speg in mitochondrial development and energy metabolism in CMs, mediated in part by phosphorylation of PGC-1α.

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Title: Striated preferentially expressed gene deficiency leads to mitochondrial dysfunction in developing cardiomyocytes
Authors: Gu Li
He Huang
Yanshuang Wu
Chang Shu
Narae Hwang
Qifei Li
Rose Zhao
Hilaire C. Lam
William M. Oldham
Souheil EI-Chemaly
Pankaj B. Agrawal
Jie Tian
Xiaoli Liu
Mark A. Perrella
Publication date: 26-12-2023
Publisher: Springer Berlin Heidelberg
Keyword: Cardiomyopathy
Published in: Basic Research in Cardiology / Issue 1/2024
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-023-01029-7

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