June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
The mitochondria-targeted peptide MTP-131 prevents hydroquinone-mediated persistent injury phenotype in cultured retinal pigment epithelium cells
Author Affiliations & Notes
  • Scott W Cousins
    Ophthalmology, Duke University School of Medicine, Durham, NC
    Immunology, Duke University School of Medicine, Durham, NC
  • Priyatham S Mettu
    Ophthalmology, Duke University School of Medicine, Durham, NC
  • Mulugu V. Brahmajothi
    Ophthalmology, Duke University School of Medicine, Durham, NC
  • Footnotes
    Commercial Relationships Scott Cousins, Stealth Peptides (F); Priyatham Mettu, None; Mulugu Brahmajothi, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 829. doi:
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      Scott W Cousins, Priyatham S Mettu, Mulugu V. Brahmajothi; The mitochondria-targeted peptide MTP-131 prevents hydroquinone-mediated persistent injury phenotype in cultured retinal pigment epithelium cells. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):829.

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

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Abstract

Purpose: Repetitive exposure of cultured retinal pigment epithelium (RPE) to the environmental toxicant hydroquinone (HQ) results in nonlethal cellular injury, characterized by blebbing and decreased extracellular matrix turnover. We hypothesize that repetitive HQ exposure promotes mitochondrial dysfunction causing persistent cellular injury, and that treatment with the mitochondria-targeted peptide MTP-131, which protects mitochondrial cardiolipin from degradation, prevents persistent injury phenotype.

Methods: ARPE19 cells were exposed to HQ (100 μM) for 6 hours, followed by 72 hour recovery phase, repeated for 4 cycles. Treated cells received MTP-131 (10 μM) daily throughout HQ exposure and recovery. At different times following HQ exposure, evidence of persistent cellular injury (hypothetically related to subRPE deposit formation) was assessed by measuring cell membrane blebbing, LDH release, cytoskeletal reorganization, MMP-2 activity, MMP-14 protein, and collagen IV synthesis. Demonstration of corresponding mitochondrial dysfunction was assessed by measuring loss of mitochondrial membrane potential, ATP production, oxygen consumption, increased ROS production (H2DCF and Mitosox), and increased FAD autofluorescence in isolated mitochondria.

Results: As expected, after single HQ exposure, cells rapidly recovered from cellular injury within 48 hours, defined as achieving 90% baseline levels of the key cellular injury indicators described above. Recovery from cell injury was associated with rapid recovery of mitochondria function. In contrast, after repetitive HQ exposure, persistent evidence of cellular injury was detected for more than a week post-HQ exposure, especially in MMP dysregulation, LDH release, and actin disorganization. Similarly, corresponding delay of mitochondria function normalization was observed, especially by persistence of increased FAD autofluorescence. MTP-131 pre-treatment prevented both persistent cellular injury and persistent mitochondrial dysfunction.

Conclusions: Repetitive HQ exposure causes chronic mitochondrial dysfunction leading to persistent injury phenotype in RPE, possibly predisposing to deposit formation. The mitochondria-directed peptide MTP-131 prevents persistent injury phenotype by preventing mitochondrial dysfunction. RPE mitochondria protection may represent a novel therapeutic strategy for dry AMD.

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