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Chemical screening identifies ROCK as a target for recovering mitochondrial function in Hutchinson-Gilford progeria syndrome

Chemical screening identifies ROCK as a target for recovering mitochondrial function in Hutchinson-Gilford progeria syndrome
Kang, Hyun TaePark, Joon TaeChoi, KobongChoi, Hyo Jei ClaudiaJung, Chul WonKim, Gyu ReeLee, Young-SamPark, Sang Chul
DGIST Authors
Lee, Young-Sam
Issued Date
Article Type
ActivationAutophagyCellsCytochrome C OxidaseCytochrome CDNA DamageDysfunctionElectron TransferFibroblastsHGPSProteinRac1bRockROSROS GenerationY 27632
Hutchinson-Gilford progeria syndrome (HGPS) constitutes a genetic disease wherein an aging phenotype manifests in childhood. Recent studies indicate that reactive oxygen species (ROS) play important roles in HGPS phenotype progression. Thus, pharmacological reduction in ROS levels has been proposed as a potentially effective treatment for patient with this disorder. In this study, we performed high-throughput screening to find compounds that could reduce ROS levels in HGPS fibroblasts and identified rho-associated protein kinase ( ROCK) inhibitor (Y-27632) as an effective agent. To elucidate the underlying mechanism of ROCK in regulating ROS levels, we performed a yeast two-hybrid screen and discovered that ROCK1 interacts with Rac1b. ROCK activation phosphorylated Rac1b at Ser71 and increased ROS levels by facilitating the interaction between Rac1b and cytochrome c. Conversely, ROCK inactivation with Y-27632 abolished their interaction, concomitant with ROS reduction. Additionally, ROCK activation resulted in mitochondrial dysfunction, whereas ROCK inactivation with Y-27632 induced the recovery of mitochondrial function. Furthermore, a reduction in the frequency of abnormal nuclear morphology and DNA double-strand breaks was observed along with decreased ROS levels. Thus, our study reveals a novel mechanism through which alleviation of the HGPS phenotype is mediated by the recovery of mitochondrial function upon ROCK inactivation.
Related Researcher
  • 이영삼 Lee, Young-Sam 뉴바이올로지학과
  • Research Interests DNA replication and repair; Restoration of cellular senescence; Structural and functional relationship of proteins
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Department of New Biology Senescence-Associated Mechanism Lab 1. Journal Articles


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