Striated preferentially expressed gene deficiency leads to mitochondrial dysfunction in developing cardiomyocytes
Gu Li1,2, He Huang3,4, Yanshuang Wu1,4
1Division of Newborn Medicine, Department of Pediatrics, Brigham and Women's Hospital, Boston, MA, 02115, USA.
Basic Research in Cardiology
|December 25, 2023
Summary
Striated preferentially expressed gene (Speg) deficiency impairs cardiomyocyte mitochondrial development and energy metabolism. This leads to abnormal mitochondrial structure, reduced ATP production, and heart failure in developing hearts.
Area of Science:
- Cardiology
- Mitochondrial Biology
- Molecular Genetics
Background:
- Striated preferentially expressed gene (Speg) deficiency causes abnormal myofibril structure and function in immature cardiomyocytes (CMs), leading to dilated cardiomyopathy, heart failure, and perinatal death.
- Mitochondrial development is crucial for cardiomyocyte maturation.
Purpose of the Study:
- To investigate the role of Speg deficiency in cardiomyocyte mitochondrial abnormalities.
- To determine if Speg impacts mitochondrial development and energy metabolism in CMs.
Main Methods:
- Utilized Speg wild-type and Speg knockout (Speg-/-) C57BL/6 mice for comparative analysis.
- Assessed mitochondrial structure using transmission electron and confocal microscopy.
- Quantified NCLX expression, mitochondrial-to-nuclear DNA ratio, ATP production, mitochondrial superoxide levels, and mitochondrial membrane potential.
Main Results:
- Speg-/- hearts showed decreased NCLX expression and mitochondrial-to-nuclear DNA ratio during embryonic development.
- Abnormal mitochondrial cristae, reduced ATP production, increased mitochondrial superoxide, and membrane potential depolarization were observed in E18.5 Speg-/- hearts.
- Phosphorylated PGC-1α (pPGC-1α) was reduced in Speg-/- hearts; Speg co-localized with PGC-1α and its kinase domain restored pPGC-1α nuclear translocation and ATP production.
Conclusions:
- Speg plays a critical role in cardiomyocyte mitochondrial development and energy metabolism.
- Speg influences mitochondrial function, at least partly, through the phosphorylation of PGC-1α.
- Speg deficiency leads to severe mitochondrial dysfunction and contributes to heart failure development.
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