Combined SIRT3 and SIRT5 deletion is associated with inner retinal dysfunction in a mouse model of type 1 diabetes

Lin, Jonathan B.; Lin, Jaw‐Ren; Chen, Howard C.; Chen, Teresa C.; Apte, Rajendra S.

doi:10.1038/s41598-019-40177-6

Cited by 23 publications

(13 citation statements)

References 31 publications

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“…In line with our observations, no developmental defects were reported. Moreover, these SIRT3/5 −/− mice were susceptible to streptozotocin-induced hyperglycemia like controls, while showing only a modest inner retinal dysfunction (61, 62).…”

Section: Discussionmentioning

confidence: 94%

Impact of the Dual Deletion of the Mitochondrial Sirtuins SIRT3 and SIRT5 on Anti-microbial Host Defenses

et al. 2019

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The sirtuins SIRT3 and SIRT5 are the main mitochondrial lysine deacetylase and desuccinylase, respectively. SIRT3 and SIRT5 regulate metabolism and redox homeostasis and have been involved in age-associated metabolic, neurologic and oncologic diseases. We have previously shown that single deficiency in either SIRT3 or SIRT5 had no impact on host defenses in a large panel of preclinical models of sepsis. However, SIRT3 and SIRT5 may compensate each other considering that they share subcellular location and targets. Here, we generated a SIRT3/5 double knockout mouse line. SIRT3/5 deficient mice multiplied and developed without abnormalities. Hematopoiesis and immune cell development were largely unaffected in SIRT3/5 deficient mice. Whole blood, macrophages and neutrophils from SIRT3/5 deficient mice displayed enhanced inflammatory and bactericidal responses. In agreement, SIRT3/5 deficient mice showed somewhat improved resistance to Listeria monocytogenes infection. Overall, the double deficiency in SIRT3 and SIRT5 has rather subtle impacts on immune cell development and anti-microbial host defenses unseen in single deficient mice, indicating a certain degree of overlap between SIRT3 and SIRT5. These data support the assumption that therapies directed against mitochondrial sirtuins, at least SIRT3 and SIRT5, should not impair antibacterial host defenses.

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Section: Discussionmentioning

confidence: 94%

Impact of the Dual Deletion of the Mitochondrial Sirtuins SIRT3 and SIRT5 on Anti-microbial Host Defenses

et al. 2019

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“…These include variants in the NAD + or NADPH dependent retinal dehydrogenases like RDH12 that cause LCA13 18 and the GTP synthesis enzyme IMPDH1 that causes retinitis pigmentosa 19,20 . SIRT3, the mitochondrial NAD + -dependent deacetylase is also important for photoreceptor homeostasis 9,21 . Together, these observations highlight the importance of cytosolic NAD + dependent pathways in retinal function 9,22 ; however, the molecular roles of nuclear NAD + and NMNAT1 in the retina are largely unknown.…”

Section: Nmnat1 Plays Important Roles In Diverse Retinal Functions Omentioning

confidence: 99%

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

Preprint

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Leber congenital amaurosis type 9 (LCA9) is an autosomal recessive, early onset retinal neurodegenerative disease caused by mutations in the gene encoding the nuclear NAD + synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1 and its role in NAD + homeostasis, LCA9 patients do not manifest pathologies other than retinal degeneration.To investigate the mechanism of degeneration, we examined retinas of developing and adult mice with conditional or tissue-specific NMNAT1 loss. Widespread NMNAT1 depletion in adult mice resulted in loss of photoreceptors, indicating these cells are exquisitely vulnerable to NMNAT1 loss. NMNAT1 is required within the photoreceptor, as conditional deletion of NMNAT1 in photoreceptors but not retinal pigment epithelial cells is sufficient to cause photoreceptor neurodegeneration and vision loss. Moreover, delivery of NMNAT1 into eyes of adult mice lacking NMNAT1 using a modified AAV8 vector containing a photoreceptor-specific promoter rescued the retinal degeneration phenotype and partially restored vision. Finally, we defined the molecular mechanism driving photoreceptor cell death. Loss of NMNAT1 activates SARM1, an inducible NADase best known as the central executioner of axon degeneration. SARM1 is required for the photoreceptor death and vision loss that occurs following NMNAT1 deletion. This surprising finding demonstrates that the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, and establishes a commonality of mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway that is active in the setting of dysregulated NAD + metabolism and identifies SARM1 as a therapeutic candidate for the treatment of retinal degeneration.

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“…These include variants in the NAD + or NADPH dependent retinal dehydrogenases like RDH12 that cause LCA13 ( Schuster et al, 2007 ) and the GTP synthesis enzyme IMPDH1 that causes retinitis pigmentosa ( Kennan et al, 2002 ; Bowne et al, 2002 ). SIRT3, the mitochondrial NAD + -dependent deacetylase is also important for photoreceptor homeostasis ( Lin et al, 2016 ; Lin et al, 2019 ). Together, these observations highlight the importance of cytosolic NAD + dependent pathways in retinal function ( Lin et al, 2016 ; Lin and Apte, 2018 ); however, the molecular roles of nuclear NAD + and NMNAT1 in the retina are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

eLife

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Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.

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Combined SIRT3 and SIRT5 deletion is associated with inner retinal dysfunction in a mouse model of type 1 diabetes

Cited by 23 publications

References 31 publications

Impact of the Dual Deletion of the Mitochondrial Sirtuins SIRT3 and SIRT5 on Anti-microbial Host Defenses

Impact of the Dual Deletion of the Mitochondrial Sirtuins SIRT3 and SIRT5 on Anti-microbial Host Defenses

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

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