Essential roles of mitochondrial biogenesis regulator Nrf1 in retinal development and homeostasis 06 Biological Sciences 0601 Biochemistry and Cell Biology 11 Medical and Health Sciences 1109 Neurosciences

Takae Kiyama, Ching Kang Chen, Steven W. Wang, Ping Pan, Zhenlin Ju, Jing Wang, Shinako Takada, William H. Klein, Chai An Mao

Research output: Contribution to journalArticle

Abstract

Background: Mitochondrial dysfunction has been implicated in the pathologies of a number of retinal degenerative diseases in both the outer and inner retina. In the outer retina, photoreceptors are particularly vulnerable to mutations affecting mitochondrial function due to their high energy demand and sensitivity to oxidative stress. However, it is unclear how defective mitochondrial biogenesis affects neural development and contributes to neural degeneration. In this report, we investigated the in vivo function of nuclear respiratory factor 1 (Nrf1), a major transcriptional regulator of mitochondrial biogenesis in both proliferating retinal progenitor cells (RPCs) and postmitotic rod photoreceptor cells (PRs). Methods: We used mouse genetic techniques to generate RPC-specific and rod PR-specific Nrf1 conditional knockout mouse models. We then applied a comprehensive set of tools, including histopathological and molecular analyses, RNA-seq, and electroretinography on these mouse lines to study Nrf1-regulated genes and Nrf1's roles in both developing retinas and differentiated rod PRs. For all comparisons between genotypes, a two-tailed two-sample student's t-test was used. Results were considered significant when P < 0.05. Results: We uncovered essential roles of Nrf1 in cell proliferation in RPCs, cell migration and survival of newly specified retinal ganglion cells (RGCs), neurite outgrowth in retinal explants, reconfiguration of metabolic pathways in RPCs, and mitochondrial morphology, position, and function in rod PRs. Conclusions: Our findings provide in vivo evidence that Nrf1 and Nrf1-mediated pathways have context-dependent and cell-state-specific functions during neural development, and disruption of Nrf1-mediated mitochondrial biogenesis in rod PRs results in impaired mitochondria and a slow, progressive degeneration of rod PRs. These results offer new insights into the roles of Nrf1 in retinal development and neuronal homeostasis and the differential sensitivities of diverse neuronal tissues and cell types of dysfunctional mitochondria. Moreover, the conditional Nrf1 allele we have generated provides the opportunity to develop novel mouse models to understand how defective mitochondrial biogenesis contributes to the pathologies and disease progression of several neurodegenerative diseases, including glaucoma, age-related macular degeneration, Parkinson's diseases, and Huntington's disease.

Original languageEnglish (US)
Article number56
JournalMolecular Neurodegeneration
Volume13
Issue number1
DOIs
StatePublished - Oct 17 2018

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Nuclear Respiratory Factor 1
Biological Science Disciplines
Organelle Biogenesis
Neurosciences
Biochemistry
Cell Biology
Homeostasis
Health
Stem Cells
Retinal Rod Photoreceptor Cells
Retina
Mitochondria
Pathology
Electroretinography
Genetic Techniques
Retinal Diseases
Retinal Ganglion Cells
Huntington Disease
Macular Degeneration
Metabolic Networks and Pathways

Keywords

  • Mitochondrial biogenesis
  • Nrf1
  • Optic atrophy
  • Photoreceptor degeneration
  • Retinal ganglion cell
  • Retinal progenitor cell

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Essential roles of mitochondrial biogenesis regulator Nrf1 in retinal development and homeostasis 06 Biological Sciences 0601 Biochemistry and Cell Biology 11 Medical and Health Sciences 1109 Neurosciences. / Kiyama, Takae; Chen, Ching Kang; Wang, Steven W.; Pan, Ping; Ju, Zhenlin; Wang, Jing; Takada, Shinako; Klein, William H.; Mao, Chai An.

In: Molecular Neurodegeneration, Vol. 13, No. 1, 56, 17.10.2018.

Research output: Contribution to journalArticle

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AU - Pan, Ping

AU - Ju, Zhenlin

AU - Wang, Jing

AU - Takada, Shinako

AU - Klein, William H.

AU - Mao, Chai An

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