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Hyperhomocysteine promotes cataract development through mTOR-mediated inhibition of autophagy and connexins

Wen-Na Liu1, Hong-Lang Huang2, Yu Lan1

  • 1Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.

International Immunopharmacology
|August 8, 2024
PubMed
Abstract

Insights

High homocysteine (Hcy) levels are linked to cataracts. This study shows Hcy disrupts autophagy and connexin expression via the mTOR pathway, potentially causing cataract development.

Area of Science:

  • Ophthalmology
  • Cell Biology
  • Biochemistry

Background:

  • Hyperhomocysteinemia is an independent risk factor for various diseases, including ocular conditions.
  • Elevated homocysteine (Hcy) levels have been implicated in eye diseases, but the specific mechanisms in cataract formation require elucidation.

Purpose of the Study:

  • To investigate the association between elevated homocysteine (Hcy) and cataract development.
  • To explore the roles of mTOR-mediated autophagy and connexin expression in Hcy-induced cataracts.

Main Methods:

  • Serum Hcy levels were measured using liquid chromatography tandem mass spectrometry in cataract patients and controls.
  • Human lens epithelial cells (HLC-B3) were treated with Hcy to analyze autophagy markers, connexin expression, and intracellular calcium.
  • Western blotting assessed phosphorylated mTOR (p-mTOR) and autophagy markers; fluorescence microscopy observed autophagic vacuoles and Ca2+.
  • Rescue experiments utilized rapamycin, an mTOR inhibitor, to reverse Hcy-induced effects.

Main Results:

  • Cataract patients exhibited significantly higher serum Hcy levels than healthy controls.
  • Hcy treatment inhibited autophagy markers (LC3B, Beclin1) and connexins (Cx43, Cx50) in HLC-B3 cells.
  • Hcy induced intracellular Ca2+ accumulation, linked to reduced connexin expression, and increased p-mTOR.
  • Rapamycin treatment rescued autophagy and connexin expression, mitigating Hcy's effects.

Conclusions:

  • Hyperhomocysteinemia may promote cataract development by dysregulating autophagy via the mTOR pathway.
  • Decreased connexin expression and subsequent intracellular calcium accumulation are implicated in Hcy-induced cataracts.
  • Targeting the mTOR pathway offers a potential therapeutic strategy for Hcy-related cataracts.
Keywords:
AutophagyCataractConnexinHomocysteinemTOR

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