title: Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative Stress.
abstract: Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration--defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsin trafficking. In an unbiased forward genetic screen designed to isolate mutations that cause photoreceptor degeneration, we identified mutations in a nuclear-encoded mitochondrial gene, ppr, a homolog of human LRPPRC. We found that ppr is required for protection against light-induced degeneration. Its function is essential to maintain membrane depolarization of the photoreceptors upon repetitive light exposure, and an impaired phototransduction cascade in ppr mutants results in excessive Rhodopsin1 endocytosis. Moreover, loss of ppr results in a reduction in mitochondrial RNAs, reduced electron transport chain activity, and reduced ATP levels. Oxidative stress, however, is not induced. We propose that the reduced ATP level in ppr mutants underlies the phototransduction defect, leading to increased Rhodopsin1 endocytosis during light exposure, causing photoreceptor degeneration independent of oxidative stress. This hypothesis is bolstered by characterization of two other genes isolated in the screen, pyruvate dehydrogenase and citrate synthase. Their loss also causes a light-induced degeneration, excessive Rhodopsin1 endocytosis and reduced ATP without concurrent oxidative stress, unlike many other mutations in mitochondrial genes that are associated with elevated oxidative stress and light-independent photoreceptor demise.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, Texas, United States of America; Howard Hughes Medical Institute, BCM, Houston, Texas, United States of America.
authors.forename: Manish
authors.initials: M
authors.lastname: Jaiswal
authors.affiliation: Program in Developmental Biology, BCM, Houston, Texas, United States of America.
authors.forename: Nele A
authors.initials: NA
authors.lastname: Haelterman
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, Texas, United States of America.
authors.forename: Hector
authors.initials: H
authors.lastname: Sandoval
authors.affiliation: Program in Developmental Biology, BCM, Houston, Texas, United States of America.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiong
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, Texas, United States of America.
authors.forename: Taraka
authors.initials: T
authors.lastname: Donti
authors.affiliation: Department of Pathology and Immunology, BCM, Houston, Texas, United States of America.
authors.forename: Auinash
authors.initials: A
authors.lastname: Kalsotra
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, Texas, United States of America; Program in Developmental Biology, BCM, Houston, Texas, United States of America; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, Texas, United States of America.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Program in Developmental Biology, BCM, Houston, Texas, United States of America; Department of Pathology and Immunology, BCM, Houston, Texas, United States of America.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Cooper
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, Texas, United States of America.
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, Texas, United States of America; Howard Hughes Medical Institute, BCM, Houston, Texas, United States of America; Program in Developmental Biology, BCM, Houston, Texas, United States of America; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, Texas, United States of America; Department of Neuroscience, BCM, Houston, Texas, United States of America.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002950:Citrate (si)-Synthase / Q000235:genetics; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004596:Electroretinography; D004705:Endocytosis; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D017956:Photoreceptor Cells, Invertebrate / Q000528:radiation effects*; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012164:Retinal Diseases / Q000235:genetics*; D012243:Rhodopsin / Q000378:metabolism; D014785:Vision, Ocular
chemical_list: D029721:Drosophila Proteins; C000597605:LRPPRC2 protein, Drosophila; D024101:Mitochondrial Proteins; D011768:Pyruvate Dehydrogenase Complex; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; C523786:bicoid stability factor, Drosophila; D000255:Adenosine Triphosphate; D012243:Rhodopsin; D002950:Citrate (si)-Synthase