June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Regulation of mitochondrial dynamics through mitofusins is essential for rod photoreceptor cell health
Author Affiliations & Notes
  • Akihiro Ikeda
    Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Michael Landowski
    Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Vijesh J. Bhute
    Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
    Chemical Engineering, Imperial College London, London, London, United Kingdom
  • Lindsay Propst
    Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Tetsuya Takimoto
    Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Sakae ikeda
    Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Footnotes
    Commercial Relationships   Akihiro Ikeda None; Michael Landowski None; Vijesh J. Bhute None; Lindsay Propst None; Tetsuya Takimoto None; Sakae ikeda None
  • Footnotes
    Support  R01EY022086, P30EY016665, F32EY032766, Timothy William Trout Chairmanship
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2422. doi:
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      Akihiro Ikeda, Michael Landowski, Vijesh J. Bhute, Lindsay Propst, Tetsuya Takimoto, Sakae ikeda; Regulation of mitochondrial dynamics through mitofusins is essential for rod photoreceptor cell health. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2422.

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

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Abstract

Purpose : Rod photoreceptor cells show uniquely arranged elongated mitochondria in inner segments and one large circular mitochondrion in each presynaptic terminal. However, it is largely unknown how those mitochondrial morphologies are developed and maintained, and what their biological significance is. We hypothesize that regulation of mitochondrial dynamics is involved in the development and maintenance of unique mitochondrial morphologies in rod photoreceptor cells. In this study, we investigated the roles of mitofusin (MFN) 1 and MFN2 in the mitochondrial morphologies and health of rod photoreceptor cells.

Methods : Eyes were collected from wild-type (WT), rhodopsin-Cre (Rho-Cre), Rho-Cre/Mfn1flx/flx, Rho-Cre/Mfn2flx/flx, and Rho-Cre/Mfn1flx/flx/Mfn2flx/flx mice at one and three months of age for histological analyses. Eyes were also collected from these genotypes at one month of age for electron microscopy analysis of mitochondrial morphologies. Lastly, neural retinas were collected from one-month-old WT and Rho-Cre/Mfn1flx/flx/Mfn2flx/flxmice for RNA-sequencing.

Results : We detected robust photoreceptor degeneration in three-month-old but not in one-month-old Rho-Cre/Mfn1flx/flx/Mfn2flx/flx mice. We also found increased mitochondrial fragmentation in rod photoreceptor inner segments and synapses of one-month-old Rho-Cre/Mfn1flx/flx/Mfn2flx/flx mice. RNA-sequencing analysis showed that 729 (427 up, 302 down) genes are differentially expressed (assessed by edgeR) in Rho-Cre/Mfn1flx/flx/Mfn2flx/flx mice compared with control mice. Through pathway analysis, we identified that genes in glycolytic pathway are down-regulated but genes involved in protein and nucleotide synthesis are up-regulated.

Conclusions : Our study indicated that MFN1 and MFN2, regulators of mitochondrial dynamics, are required for development and/or maintenance of mitochondrial morphologies in rod photoreceptor cells in mice, which in turn is essential for the maintenance of rod photoreceptor cells. Changes in mitochondrial dynamics/ morphology result in reduced glycolysis as well as increased protein/nucleotide synthesis, which may affect the metabolic status of rod photoreceptor cells.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

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