The ESCRT protein CHMP5 restrains skeletal progenitor cell senescence by preserving endo-lysosomal-mitochondrial network

Abstract

AbstractThe endocytic pathway actively interacts with mitochondria in maintaining cellular homeostasis. However, how the dysfunction of this inter-organelle interaction causing pathological outcomes remains less understood. Here we show that an aberrant endocytic pathway from the deficiency of CHMP5 in skeletal progenitor cells causes accumulation of functionally compromised mitochondria, which induce cellular senescence via reactive oxygen species (ROS)-mediated oxidative stress and DNA damage. These senescent progenitors can lead to distorted skeletal growth via a combination of cell-autonomous and non-autonomous mechanisms. Consequently, mice lacking Chmp5 in Ctsk-expressing periskeletal progenitors or Dmp1-expressing musculoskeletal progenitors develop multiple skeletal/muscular abnormalities, including robust bone overgrowth, progressive joint stiffness, and myopathy. Targeting senescent cells using senolytic drugs significantly alleviates these lesions and improves animal motility. Overall, our results reveal that CHMP5 restricts skeletal progenitor cell senescence through maintaining the endo-lysosomal-mitochondrial network and cell senescence represents a yet unexplored mechanism for detrimental alterations from the perturbed organelle network.