Cardiac-specific deletion of heat shock protein 60 induces mitochondrial stress and disrupts heart development in mice

Biochem Biophys Res Commun. 2024 May 28:710:149883. doi: 10.1016/j.bbrc.2024.149883. Epub 2024 Apr 4.

Abstract

Congenital heart diseases are the most common birth defects around the world. Emerging evidence suggests that mitochondrial homeostasis is required for normal heart development. In mitochondria, a series of molecular chaperones including heat shock protein 60 (HSP60) are engaged in assisting the import and folding of mitochondrial proteins. However, it remains largely obscure whether and how these mitochondrial chaperones regulate cardiac development. Here, we generated a cardiac-specific Hspd1 deletion mouse model by αMHC-Cre and investigated the role of HSP60 in cardiac development. We observed that deletion of HSP60 in embryonic cardiomyocytes resulted in abnormal heart development and embryonic lethality, characterized by reduced cardiac cell proliferation and thinner ventricular walls, highlighting an essential role of cardiac HSP60 in embryonic heart development and survival. Our results also demonstrated that HSP60 deficiency caused significant downregulation of mitochondrial ETC subunits and induced mitochondrial stress. Analysis of gene expression revealed that P21 that negatively regulates cell proliferation is significantly upregulated in HSP60 knockout hearts. Moreover, HSP60 deficiency induced activation of eIF2α-ATF4 pathway, further indicating the underlying mitochondrial stress in cardiomyocytes after HSP60 deletion. Taken together, our study demonstrated that regular function of mitochondrial chaperones is pivotal for maintaining normal mitochondrial homeostasis and embryonic heart development.

Keywords: ATF4; Cardiomyocytes; Heart development; Heat shock protein 60; Mitochondrial stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chaperonin 60* / genetics
  • Chaperonin 60* / metabolism
  • Heart Defects, Congenital* / metabolism
  • Mice
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Myocytes, Cardiac / metabolism

Substances

  • Chaperonin 60
  • Mitochondrial Proteins
  • Molecular Chaperones
  • Hspd1 protein, mouse