June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Dynein Dysregulation Due to the Absence of NUDC leads to Mitochondrial Mislocalization and Dysfunction in Rod Photoreceptors
Author Affiliations & Notes
  • Hailey Jori Levi
    Neurobiology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Meredith Hubbard
    Neurobiology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Mary Anne Garner
    Neurobiology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • TJ Hollingsworth
    Ophthalmology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Ke Jiang
    Neurobiology Neurodegeneration & Repair Laboratory, National Eye Institute, Bethesda, Maryland, United States
  • Nat Nelson
    Ophthalmology/Visual Science, The University of Utah, Salt Lake City, Utah, United States
  • Anushree Gade
    Neurobiology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Drue Benefield
    Medicine, Division of Cardiovascular Disease, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Guoxin Ying
    Ophthalmology/Visual Science, The University of Utah, Salt Lake City, Utah, United States
  • Wolfgang Baehr
    Ophthalmology/Visual Science, The University of Utah, Salt Lake City, Utah, United States
  • Bryan W. Jones
    Ophthalmology/Visual Science, The University of Utah, Salt Lake City, Utah, United States
  • Anand Swaroop
    Neurobiology Neurodegeneration & Repair Laboratory, National Eye Institute, Bethesda, Maryland, United States
  • Glenn Rowe
    Medicine, Division of Cardiovascular Disease, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Alecia K Gross
    Neurobiology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Footnotes
    Commercial Relationships   Hailey Levi None; Meredith Hubbard None; Mary Anne Garner None; TJ Hollingsworth None; Ke Jiang None; Nat Nelson None; Anushree Gade None; Drue Benefield None; Guoxin Ying None; Wolfgang Baehr None; Bryan Jones None; Anand Swaroop None; Glenn Rowe None; Alecia Gross None
  • Footnotes
    Support  NIH Grants EY030096, EY019311, ZIAEY000450, ZIAEY000546
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 3878 – A0080. doi:
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      Hailey Jori Levi, Meredith Hubbard, Mary Anne Garner, TJ Hollingsworth, Ke Jiang, Nat Nelson, Anushree Gade, Drue Benefield, Guoxin Ying, Wolfgang Baehr, Bryan W. Jones, Anand Swaroop, Glenn Rowe, Alecia K Gross; Dynein Dysregulation Due to the Absence of NUDC leads to Mitochondrial Mislocalization and Dysfunction in Rod Photoreceptors. Invest. Ophthalmol. Vis. Sci. 2022;63(7):3878 – A0080.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Mitochondrial stress impairs the function of photoreceptors and can lead to retinal degeneration and blindness. Microtubules and the cytoplasmic dynein complex are necessary for proper trafficking and localization of cargo, including mitochondria. We have identified Nuclear Distribution Protein C (NUDC), a known regulator of cytoplasmic dynein, to be critical in rod and cone photoreceptor health. We hypothesize that the absence of NUDC causes a dysregulation in dynein movement along microtubules leading to mitochondrial and protein mislocalization, as well as cellular stress and cell death.

Methods : We generated a floxed Nudc mouse and bred it to the rod-specific Opsin-iCre75 mouse to produce Nudc+/- or Nudc-/- in rods. To characterize the effect of NUDC loss on mitochondria in the retina of these mice, we performed a combination of assays including: Optical Coherence Tomography (OCT) to uncover retinal thickness in vivo; Transmission Electron Microscopy (TEM) to investigate the ultrastructure of mitochondria in rods; quantitative RT-PCR (qRT-PCR) to measure changes in transcripts of selected mitochondrial genes; immunohistochemistry (IHC) to reveal localization of key proteins involved in phototransduction, mitochondrial fission/fusion, and unfolded protein response (UPR) pathways; and seahorse assays to assess mitochondrial respiration in freshly dissected ex vivo retinal tissues.

Results : At P21, OCT analysis revealed retinal degeneration progressing through P42. TEM demonstrated an increased number of mitochondria scattered throughout the inner segment in Nudc-/- rods, rather than localized in the ellipsoid as in wild type. qRT-PCR showed no change or decrease in mRNA levels of genes associated with mitochondrial fission, but IHC revealed an upregulation of gliosis via GFAP in Müller glia and rhodopsin mislocalization in photoreceptors in the absence of NUDC. Additionally, altered mitochondrial respiration and mitochondrial reserve capacity were observed with Nudc deletion in P21 rods.

Conclusions : We have demonstrated that, in the absence of NUDC, mitochondria are mislocalized and exhibit compromised function in rod photoreceptors. We detect an upregulation of proteins involved in the UPR and in the inflammatory response concomitant with retinal degeneration, underscoring the importance of microtubule trafficking by NUDC in the overall health of photoreceptors.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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