title: Small Molecules that Protect Mitochondrial Function from Metabolic Stress Decelerate Loss of Photoreceptor Cells in Murine Retinal Degeneration Models.
abstract: One feature common to many of the pathways implicated in retinal degeneration is increased metabolic stress leading to impaired mitochondrial function. We found that exposure of cells to calcium ionophores or oxidants as metabolic stressors diminish maximal mitochondrial capacity. A library of 50,000 structurally diverse "drug-like" molecules was screened for protection against loss of calcium-induced loss of mitochondrial capacity in 661W rod-derived cells and C6 glioblastomas. Initial protective hits were then tested for protection against IBMX-induced loss of mitochondrial capacity as measured via respirometry. Molecules that protected mitochondria were then evaluated for protection of rod photoreceptor cells in retinal explants from rd1 mice. Two of the molecules attenuated loss of photoreceptor cells in the rd1 model. In the 661W cells, exposure to calcium ionophore or tert-butylhydroperoxide caused mitochondrial fragmentation that was blocked with the both compounds. Our studies have identified molecules that protect mitochondria and attenuate loss of photoreceptors in models of retinal degeneration suggesting that they could be good leads for development of therapeutic drugs for treatment of a wide variety of retinal dystrophies.
authors.affiliation: MitoChem Therapeutics Inc, 280 Calhoun Street, MSC140, 29403, Charleston, SC, USA. beesonc@musc.edu.|Departments of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 29425, Charleston, SC, USA. beesonc@musc.edu.
authors.forename: Craig
authors.initials: C
authors.lastname: Beeson
authors.affiliation: MitoChem Therapeutics Inc, 280 Calhoun Street, MSC140, 29403, Charleston, SC, USA. lindseyc@musc.edu.|Departments of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 29425, Charleston, SC, USA. lindseyc@musc.edu.
authors.forename: Chris
authors.initials: C
authors.lastname: Lindsey
authors.affiliation: Departments of Ophthalmology, Medical University of South Carolina, 29425, Charleston, SC, USA. nassarre@musc.edu.
authors.forename: Cecile
authors.initials: C
authors.lastname: Nasarre
authors.affiliation: Departments of Ophthalmology, Medical University of South Carolina, 29425, Charleston, SC, USA. bandyom@musc.edu.
authors.forename: Mausumi
authors.initials: M
authors.lastname: Bandyopadhyay
authors.affiliation: Departments of Ophthalmology, Medical University of South Carolina, 29425, Charleston, SC, USA. perron@musc.edu.
authors.forename: Nathan
authors.initials: N
authors.lastname: Perron
authors.affiliation: Departments of Ophthalmology, Medical University of South Carolina, 29425, Charleston, SC, USA. rohrer@musc.edu.|Division of Research, Ralph H. Johnson VA Medical Center, 29401, Charleston, SC, USA. rohrer@musc.edu.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Rohrer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D006019:Glycolysis / Q000187:drug effects; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D020011:Protective Agents; D054852:Small Molecule Libraries
keywords: ATP; Glycolysis; Mitochondria; Neuroprotectant; Respirometry