September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Mitochondrial Dysfunction in Experimental Mouse Models of SubRPE Deposit Formation and Reversal by the Mito-Reparative Drug MTP-131
Author Affiliations & Notes
  • Scott W Cousins
    Ophthalmology, Duke University School of Medicine, Durham, North Carolina, United States
    Immunology, Duke University School of Medicine, Durham, North Carolina, United States
  • Peter Saloupis
    Ophthalmology, Duke University School of Medicine, Durham, North Carolina, United States
  • Mulugu V. Brahmajoti
    Ophthalmology, Duke University School of Medicine, Durham, North Carolina, United States
  • Priyatham S Mettu
    Ophthalmology, Duke University School of Medicine, Durham, North Carolina, United States
  • Footnotes
    Commercial Relationships   Scott Cousins, Stealth BioTherapeutics (F), Stealth BioTherapeutics (C); Peter Saloupis, None; Mulugu Brahmajoti, None; Priyatham Mettu, None
  • Footnotes
    Support  Stealth BioTherapeutics (SWC), Research to Prevent Blindness Unrestricted Grant (SWC, PSM), 5P30EY005722-28 NEI Core Grant (SWC, PSM), NEI 1K08 EY025325-01 (PSM)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2126. doi:
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      Scott W Cousins, Peter Saloupis, Mulugu V. Brahmajoti, Priyatham S Mettu; Mitochondrial Dysfunction in Experimental Mouse Models of SubRPE Deposit Formation and Reversal by the Mito-Reparative Drug MTP-131. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2126.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : To investigate the role of mitochondrial dysfunction in subRPE deposit formation in mouse models of dry AMD and to assess the response to treatment with MTP-131, a mitochondria-targeting drug that can reverse pre-existing dysfunction.

Methods : An acute model of subRPE deposits was generated in young BALB/c or C57BL6/J mice receiving biweekly subconjunctival injection of the environmental toxicant hydroquinone (HQ, 25 μL, 75 mM, administered over 2 or 4 weeks). Chronic subRPE deposits were evaluated in ApoE4 transgenic mice fed high fat + cholesterol (HFC) diet for 4 months. Morphology was assessed by transmission electron microscopy. Fluorescence confocal microscopy of RPE flatmounts was used to assess (1) mitochondrial dysfunction (flavoprotein autofluorescence (FP-AF) and superoxide); (2) activation of signaling cascades (pHSP25); and (3) biochemical mediators of subRPE deposit formation (actin cytoskeleton disruption and vimentin upregulation). Subcutaneous MTP-131 (3 mg/kg) was given at various times after onset of mitochondrial dysfunction.

Results : Acute model: subconjunctival HQ produced frequency-dependent accumulation of subRPE deposits, appearing as precursors to deposits observed in chronic models. Simultaneous with deposits, we observed (1) increased FP-AF and superoxide production, (2) increased pHSP25, and (3) actin aggregate formation. MTP-131 reversed pre-existing HQ-induced mitochondria dysfunction and the associated biochemical responses. Chronic model: in ApoE4 mice fed HFC diet, we observed characteristic subRPE deposits in association with (1) mitochondrial dysfunction (intense FP-AF and high superoxide) and (2) activation of deposit mediators (disrupted actin cytoskeleton and increased vimentin expression). Further, in the ApoE4 model, mitochondrial dysfunction was also reversed by MTP-131 in association with improvement in deposit mediators.

Conclusions : In several mouse models of deposits, mitochondrial dysfunction appears to be a trigger of subRPE deposit formation; reversal of dysfunction with MTP-131 also reverses prior activation of signaling cascades and biochemical mediators of deposits. Mitochondrial dysfunction may be a generalized paradigm for dry AMD pathogenesis, and mitochondria-targeting drugs may be therapeutic for dry AMD.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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