title: PGC-1α determines light damage susceptibility of the murine retina.
abstract: The peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) proteins are key regulators of cellular bioenergetics and are accordingly expressed in tissues with a high energetic demand. For example, PGC-1α and PGC-1β control organ function of brown adipose tissue, heart, brain, liver and skeletal muscle. Surprisingly, despite their prominent role in the control of mitochondrial biogenesis and oxidative metabolism, expression and function of the PGC-1 coactivators in the retina, an organ with one of the highest energy demands per tissue weight, are completely unknown. Moreover, the molecular mechanisms that coordinate energy production with repair processes in the damaged retina remain enigmatic. In the present study, we thus investigated the expression and function of the PGC-1 coactivators in the healthy and the damaged retina. We show that PGC-1α and PGC-1β are found at high levels in different structures of the mouse retina, most prominently in the photoreceptors. Furthermore, PGC-1α knockout mice suffer from a striking deterioration in retinal morphology and function upon detrimental light exposure. Gene expression studies revealed dysregulation of all major pathways involved in retinal damage and apoptosis, repair and renewal in the PGC-1α knockouts. The light-induced increase in apoptosis in vivo in the absence of PGC-1α was substantiated in vitro, where overexpression of PGC-1α evoked strong anti-apoptotic effects. Finally, we found that retinal levels of PGC-1 expression are reduced in different mouse models for retinitis pigmentosa. We demonstrate that PGC-1α is a central coordinator of energy production and, importantly, all of the major processes involved in retinal damage and subsequent repair. Together with the observed dysregulation of PGC-1α and PGC-1β in retinitis pigmentosa mouse models, these findings thus imply that PGC-1α might be an attractive target for therapeutic approaches aimed at retinal degeneration diseases.
authors.affiliation: Biozentrum, Division of Pharmacology/Neurobiology, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Egger
authors.forename: Marijana
authors.initials: M
authors.lastname: Samardzija
authors.forename: Vithiyanjali
authors.initials: V
authors.lastname: Sothilingam
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tanimoto
authors.forename: Christina
authors.initials: C
authors.lastname: Lange
authors.forename: Silvia
authors.initials: S
authors.lastname: Salatino
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.forename: Marina
authors.initials: M
authors.lastname: Garcia-Garrido
authors.forename: Susanne
authors.initials: S
authors.lastname: Beck
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Okoniewski
authors.forename: Albert
authors.initials: A
authors.lastname: Neutzner
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
authors.forename: Christoph
authors.initials: C
authors.lastname: Handschin
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004734:Energy Metabolism; D020869:Gene Expression Profiling; D008027:Light / Q000009:adverse effects*; D051379:Mice; D010786:Photoreceptor Cells / Q000737:chemistry; D012160:Retina / Q000737:chemistry / Q000293:injuries / Q000473:pathology / Q000528:radiation effects*; D012173:Retinitis; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*; D014945:Wound Healing
chemical_list: D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1