Sirtuins are NAD+-dependent enzymes that govern cellular homeostasis by regulating the acylation status of their diverse target proteins. We recently demonstrated that both rod and cone photoreceptors rely on NAMPT-mediated NAD+ biosynthesis to meet their energetic requirements. Moreover, we found that this NAD+-dependent retinal homeostasis relies, in part, on maintenance of optimal activity of the mitochondrial sirtuins and of SIRT3 in particular. Nonetheless, it is unknown whether other sirtuin family members also play important roles in retinal homeostasis. Our results suggest that SIRT1, SIRT2, SIRT4, and SIRT6 are dispensable for retinal survival at baseline, as individual deletion of each of these sirtuins does not cause retinal degeneration by fundus biomicroscopy or retinal dysfunction by ERG. These findings have significant implications and inform future studies investigating the mechanisms underlying the central role of NAD+ biosynthesis in retinal survival and function.
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This work was supported by NIH Grants R01 EY019287 (R.S.A.) and P30 EY02687 (Vision Core Grant); the C.M. and M.A. Reeves Foundation (R.S.A.); Research to Prevent Blindness (R.S.A.); the Hope Center (R.S.A.); the Lacy Foundation (S.K.); the Schulak Family Gift Fund for Retinal Research (R.S.A.); the Jeffrey Fort Innovation Fund (R.S.A.); and the Robert Machemer Foundation (S.K.). Additional funding comes from an unrestricted grant to the Department of Ophthalmology and Visual Sciences of Washington University School of Medicine from Research to Prevent Blindness. J.B.L. was supported by the Washington University in St. Louis Medical Scientist Training Program (NIH Grant T32 GM007200), the Washington University in St. Louis Institute of Clinical and Translational Sciences (NIH Grants UL1 TR000448, TL1 TR000449), the Washington University Diabetic Cardiovascular Disease Center, the American Federation for Aging Research, and the VitreoRetinal Surgery Foundation.
Hirschey MD, Shimazu T, Jing E et al (2011) SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell 44:177–190CrossRefPubMedPubMedCentralGoogle Scholar
Liszt G, Ford E, Kurtev M et al (2005) Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem 280:21313–21320CrossRefPubMedGoogle Scholar
Mattapallil MJ, Wawrousek EF, Chan CC et al (2012) The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL/6N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes. Invest Ophthalmol Vis Sci 53:2921–2927CrossRefPubMedPubMedCentralGoogle Scholar
Michishita E, Park JY, Burneskis JM et al (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell 16:4623–4635CrossRefPubMedPubMedCentralGoogle Scholar
Mostoslavsky R, Chua KF, Lombard DB et al (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124:315–329CrossRefPubMedGoogle Scholar
Schwer B, North BJ, Frye RA et al (2002) The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol 158:647–657CrossRefPubMedPubMedCentralGoogle Scholar