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Aging Cell. 2017 Jun;16(3):541-550. doi: 10.1111/acel.12584. Epub 2017 Mar 19.

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

Author information

1
Well Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon-si, Korea.
2
Well Aging Research Center, DGIST, Daegu, Korea.
3
Department of New Biology, DGIST, Daegu, Korea.

Abstract

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.

KEYWORDS:

HGPS ; ROCK ; ROS ; Cytochrome c; Rac1b; Y-27632

PMID:
28317242
PMCID:
PMC5418208
DOI:
10.1111/acel.12584
[Indexed for MEDLINE]
Free PMC Article

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