Homocysteine-mediated modulation of mitochondrial dynamics in retinal ganglion cells

Preethi S. Ganapathy, Richard L. Perry, Amany Mohamed Tawfik, Robert M. Smith, Elizabeth Perry, Penny Roon, B. Renee Bozard, Yonju Ha, Sylvia B Smith

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Purpose. To evaluate the effect of excess homocysteine on the regulation of retinal ganglion cell mitochondrial dynamics. Methods. Mice deficient in cystathionine-β-synthase (cbs) were used as a model of hyperhomocysteinemia. Gene and protein expression analyses of Opa1 and Fis1 were performed on cbs +/- neural retinas. Mitochondria within retinal ganglion cell axons underwent systematic ultrastructural analysis to measure area, length, width, and the distance between the mitochondria and the axon wall. Primary mouse ganglion cells were cultured, treated with homocysteine, and assessed for levels of Opa1 and Fis1 protein, the number of mitochondria per length of neurite, and levels of cleaved caspase-3. Results. Opa1 and Fis1 protein levels in cbs +/- neural retinas were elevated to 191.00% ± 26.40% and 226.20% ± 4.57%, respectively, compared with wild-type. Mitochondria of cbs +/- retinas were smaller in all parameters studied, including area (0.32±0.01μm 2 vs. 0.42±0.02μm 2), compared with wild-type. Primary ganglion cells treated with homocysteine had elevations in Opa1 and Fis1 proteins, a significantly higher number of mitochondria per length of neurite (0.1781 ± 0.017 vs. 0.1156 ± 0.012), and significantly higher levels of cleaved caspase-3 compared with control. Conclusions. This study provides the first evidence that homocysteine- induced ganglion cell loss involves the dysregulation of mitochondrial dynamics, both in vivo and in vitro. The present data suggest increased mitochondrial fission as a novel mechanism of homocysteine toxicity to neurons. Of particular relevance are glaucoma and Alzheimer's disease, neurodegenerative diseases that are associated with hyperhomocysteinemia and, more recently, have implicated increased mitochondrial fission in their pathogeneses.

Original languageEnglish (US)
Pages (from-to)5551-5558
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume52
Issue number8
DOIs
StatePublished - Jul 2011

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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