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Vadivel Ganapathy, Pachiappan Arjunan, Jaya Pranava Gnana Prakasam, Sylvia B Smith, Pamela M Martin, ; Mitochondrial histone deacetylase Sirt3 as a regulator of iron homeostasis and metabolite receptors Gpr91 and Gpr81 in retina . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):59.
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SIRT3 is a mitochondrial histone deacetylase critical for the optimal maintenance of mitochondrial metabolic pathways (e.g., citric acid cycle, oxidative phosphorylation, and urea cycle). Deletion of Sirt3 in mice leads to defective mitochondrial function. We hypothesized that Sirt3 may also play a role in iron homeostasis because chelation of iron into heme occurs only in mitochondria. Since mitochondrial activity controls tissue levels of succinate and lactate, we also predicted that Sirt3 may regulate the expression of Gpr91 and Gpr81, the receptors for succinate and lactate, respectively.
We used wild type (WT) and Sirt3-null mice to monitor the iron status in retinal sections by immunofluorescence analysis of ferritin. Retinal expression of Gpr91 and Gpr81 was monitored by immunofluorescence (protein) and qPCR (mRNA). Since changes in mitochondrial activity also reflect oxygen availability, we examined the expression of HIF-1alpha and its target gene VEGF in WT and Sirt3-null retinal sections by immunofluorescence. To determine if alterations in iron status impact on Sirt3, we compared the expression of Sirt3 (immunofluorescence and qPCR) in retina and RPE cells in WT and Hfe-null mice, a model for the iron-overload disease hemochromatosis.
Sirt3 is expressed widely in the retina. Deletion of Sirt3 increases the expression of the heavy and light chains of ferritin, a hallmark of iron overload. There is also increased expression of HIF-1alpha and VEGF. In accordance with the expected increase in the tissue levels of succinate and lactate in Sirt3-null mice, the expression of Gpr91 and Gpr81 is also increased in Sirt3-null mouse retinas. In addition, Sirt3 expression is influenced by iron status as evident from decreased expression of Sirt3 in retina and RPE from Hfe-null mice.
Sirt3 is a regulator of iron homeostasis in retina; retinal iron levels increase in Sirt3-null mice. Deletion of Sirt3 mimics hypoxia. Sirt3 also controls the expression of Gpr91 and Gpr81 in coordination with the tissue levels of their agonists succinate and lactate. Conversely, excessive iron in retina suppresses Sirt3 expression. These data suggest that Sirt3 is an important determinant of iron homeostasis and also signaling via the pro-angiogenic receptors Gpr91 and Gpr81 in the retina.
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