Redox Regulation of Mitochondrial Fission Protein Drp1 by Protein Disulfide Isomerase Limits Endothelial Senescence

Young-Mee Kim, Seock Won Youn, Sudhahar Varadarajan, Archita Das, Reyhaan Chandhri, Henar Cuervo Grajal, Junghun Kweon, Silvia Leanhart, Lianying He, Peter T. Toth, Jan Kitajewski, Jalees Rehman, Yisang Yoon, Jaehyung Cho, Tohru Fukai, Masuko Fukai

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Mitochondrial dynamics are tightly controlled by fusion and fission, and their dysregulation and excess reactive oxygen species (ROS) contribute to endothelial cell (EC) dysfunction. How redox signals regulate coupling between mitochondrial dynamics and endothelial (dys)function remains unknown. Here, we identify protein disulfide isomerase A1 (PDIA1) as a thiol reductase for the mitochondrial fission protein Drp1. A biotin-labeled Cys-OH trapping probe and rescue experiments reveal that PDIA1 depletion in ECs induces sulfenylation of Drp1 at Cys644, promoting mitochondrial fragmentation and ROS elevation without inducing ER stress, which drives EC senescence. Mechanistically, PDIA1 associates with Drp1 to reduce its redox status and activity. Defective wound healing and angiogenesis in diabetic or PDIA1+/− mice are restored by EC-targeted PDIA1 or the Cys oxidation-defective mutant Drp1. Thus, this study uncovers a molecular link between PDIA1 and Drp1 oxidoreduction, which maintains normal mitochondrial dynamics and limits endothelial senescence with potential translational implications for vascular diseases associated with diabetes or aging. Kim et al. demonstrate a molecular link between PDIA1 and Drp1 oxidoreduction, which protects against mitochondrial fragmentation and ROS elevation, limiting endothelial senescence. This study provides insights into restoring endothelial PDIA1 function or targeting Drp1 Cys oxidation as potential therapeutic strategies for treating diabetes-associated vascular and metabolic diseases.

Original languageEnglish (US)
Pages (from-to)3565-3578
Number of pages14
JournalCell Reports
Volume23
Issue number12
DOIs
StatePublished - Jun 19 2018

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Keywords

  • Drp1
  • angiogenesis
  • diabetes
  • endothelial dysfunction
  • endothelial senescence
  • mitochondrial fission
  • protein disulfide isomerase
  • reactive oxygen species
  • sulfenylation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kim, Y-M., Youn, S. W., Varadarajan, S., Das, A., Chandhri, R., Cuervo Grajal, H., Kweon, J., Leanhart, S., He, L., Toth, P. T., Kitajewski, J., Rehman, J., Yoon, Y., Cho, J., Fukai, T., & Fukai, M. (2018). Redox Regulation of Mitochondrial Fission Protein Drp1 by Protein Disulfide Isomerase Limits Endothelial Senescence. Cell Reports, 23(12), 3565-3578. https://doi.org/10.1016/j.celrep.2018.05.054