Aberrant mitochondrial hsp60 expression affects mitochondria homeostasis and results in muscle dystrophy and premature death.

Heat shock protein 60 (HSP60) plays a vital role in maintaining mitochondrial homeostasis and essential functions and requires ATP for its assembly into chaperone complexes. This study aimed to investigate the long-term effects of HSP60 induction on mitochondrial homeostasis at varying doses and durations using HSP60 transgenic mice. In this study, we generated transgenic mice with elevated levels of native HSP60 using the LoxP-Cre system. These mice exhibited impaired postnatal development, skeletal muscle dystrophy, and increased mortality. Initially, excess HSP60 enhanced the mitochondrial oxidative respiratory capacity, which was later compensated for by increased glycolysis. Surplus HSP60 primarily accumulated in the mitochondria, likely due to insufficient ATP availability, leading to the buildup of HSP60 heptamers. Consequently, mitochondrial number and morphology were altered, protein levels in electron transport chain complexes were reduced, and oxidative phosphorylation was impaired. Additionally, reactive oxygen species accumulated, contributing to mitochondrial dysfunction in skeletal muscles. The upregulation of Pink-1/Parkin triggered enhanced autophagy, while increased Bax and poly (ADP-ribose) polymerase (PARP) cleavage mediated heightened apoptosis; both mechanisms aimed at eliminating damaged mitochondria. However, prolonged HSP60 accumulation overwhelmed these protective processes, ultimately leading to skeletal muscle dystrophy and premature death. Our findings demonstrated that excessive mitochondrial HSP60 initially boosts oxidative respiration; however, over time, it contributes to mitochondrial dysregulation and myopathy. This study provides novel insights into how excessive HSP60 affects mitochondrial oxidative respiration and glycolysis, with potential links to certain mitochondria-related diseases.