Dilated cardiomyopathy-linked heat shock protein family D member 1 mutations cause up-regulation of reactive oxygen species and autophagy through mitochondrial dysfunction. Academic Article uri icon

Overview

abstract

  • AIMS: During heart failure, the levels of circulatory heat shock protein family D member 1 (HSP60) increase. However, its underlying mechanism is still unknown. The apical domain of heat shock protein family D member 1 (HSPD1) is conserved throughout evolution. We found a point mutation in HSPD1 in a familial dilated cardiomyopathy (DCM) patient. A similar point mutation in HSPD1 in the zebrafish mutant, nbl, led to loss of its regenerative capacity and development of pericardial oedema under heat stress condition. In this study, we aimed to determine the direct involvement of HSPD1 in the development of DCM. METHODS AND RESULTS: By Sanger method, we found a point mutation (Thr320Ala) in the apical domain of HSPD1, in one familial DCM patient, which was four amino acids away from the point mutation (Val324Glu) in the nbl mutant zebrafish. The nbl mutants showed atrio-ventricular block and sudden death at 8-month post-fertilization. Histological and microscopic analysis of the nbl mutant hearts showed decreased ventricular wall thickness, elevated level of reactive oxygen species (ROS), increased fibrosis, mitochondrial damage, and increased autophagosomes. mRNA and protein expression of autophagy-related genes significantly increased in nbl mutants. We established HEK293 stable cell lines of wild-type, nbl-type, and DCM-type HSPD1, with tetracycline-dependent expression. Compared to wild-type, both nbl- and DCM-type cells showed decreased cell growth, increased expression of ROS and autophagy-related genes, inhibition of the activity of mitochondrial electron transport chain complexes III and IV, and decreased mitochondrial fission and fusion. CONCLUSION: Mutations in HSPD1 caused mitochondrial dysfunction and induced mitophagy. Mitochondrial dysfunction caused increased ROS and cardiac atrophy.

publication date

  • March 21, 2021

Research

keywords

  • Autophagy
  • Cardiomyopathy, Dilated
  • Chaperonin 60
  • Mitochondria, Heart
  • Mitochondrial Proteins
  • Myocytes, Cardiac
  • Nerve Tissue Proteins
  • Oxidative Stress
  • Point Mutation
  • Reactive Oxygen Species
  • Zebrafish Proteins

Identity

Scopus Document Identifier

  • 85103474227

Digital Object Identifier (DOI)

  • 10.1093/cvr/cvaa158

PubMed ID

  • 32520982

Additional Document Info

volume

  • 117

issue

  • 4