Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by Vitamin B supplementation.

Journal Article (Journal Article)

Hyperhomocysteinemia (HHcy) is a well-known risk factor for stroke; however, its underlying molecular mechanism remains unclear. Using both mouse and cell culture models, we have provided evidence that impairment of autophagy has a central role in HHcy-induced cellular injury in the mouse brain. We observed accumulation of LC3B-II and p62 that was associated with increased MTOR signaling in human and mouse primary astrocyte cell cultures as well as a diet-induced mouse model of HHcy, HHcy decreased lysosomal membrane protein LAMP2, vacuolar ATPase (ATP6V0A2), and protease cathepsin D, suggesting that lysosomal dysfunction also contributed to the autophagic defect. Moreover, HHcy increased unfolded protein response. Interestingly, Vitamin B supplementation restored autophagic flux, alleviated ER stress, and reversed lysosomal dysfunction due to HHCy. Furthermore, the autophagy inducer, rapamycin was able to relieve ER stress and reverse lysosomal dysfunction caused by HHcy in vitro. Inhibition of autophagy by HHcy exacerbated cellular injury during oxygen and glucose deprivation and reperfusion (OGD/R), and oxidative stress. These effects were prevented by Vitamin B co-treatment, suggesting that it may be helpful in relieving detrimental effects of HHcy in ischemia/reperfusion or oxidative stress. Collectively, these findings show that Vitamin B therapy can reverse defects in cellular autophagy and ER stress due to HHcy; and thus may be a potential treatment to reduce ischemic damage caused by stroke in patients with HHcy.

Full Text

Duke Authors

Cited Authors

  • Tripathi, M; Zhang, CW; Singh, BK; Sinha, RA; Moe, KT; DeSilva, DA; Yen, PM

Published Date

  • December 8, 2016

Published In

Volume / Issue

  • 7 / 12

Start / End Page

  • e2513 -

PubMed ID

  • 27929536

Pubmed Central ID

  • PMC5260994

Electronic International Standard Serial Number (EISSN)

  • 2041-4889

Digital Object Identifier (DOI)

  • 10.1038/cddis.2016.374


  • eng

Conference Location

  • England