Improving retinal mitochondrial function as a treatment for age-related macular degeneration

Mara C. Ebeling, Jorge R. Polanco, Jun Qu, Chengjian Tu, Sandra R. Montezuma, Deborah A. Ferrington

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Currently, there are no treatments for dry AMD, which is characterized by the death of retinal pigment epithelium (RPE) and photoreceptors. Reports from human donors with AMD suggest that RPE mitochondrial defects are a key event in AMD pathology. Thus, the most effective strategy for treating dry AMD is to identify compounds that enhance mitochondrial function and subsequently, preserve the RPE. In this study, primary cultures of RPE from human donors with (n = 20) or without (n = 8) AMD were used to evaluate compounds that are designed to protect mitochondria from oxidative damage (N-acetyl-L-cysteine; NAC), remove damaged mitochondria (Rapamycin), increase mitochondrial biogenesis (Pyrroloquinoline quinone; PQQ), and improve oxidative phosphorylation (Nicotinamide mononucleotide, NMN). Mitochondrial function measured after drug treatments showed an AMD-dependent response; only RPE from donors with AMD showed improvements. All four drugs caused a significant increase in maximal respiration (p < 0.05) compared to untreated controls. Treatment with Rapamycin, PQQ, or NMN significantly increased ATP production (p < 0.05). Only Rapamycin increased basal respiration (p < 0.05). Notably, robust responses were observed in only about 50% of AMD donors, with attenuated responses observed in the remaining AMD donors. Further, within the responders, individual donors exhibited a distinct reaction to each drug. Our results suggest drugs targeting pathways involved in maintaining healthy mitochondria can improve mitochondrial function in a select population of RPE from AMD donors. The unique response of individual donors to specific drugs supports the need for personalized medicine when treating AMD.

Original languageEnglish (US)
Article number101552
JournalRedox Biology
Volume34
DOIs
StatePublished - Jul 2020

Bibliographical note

Funding Information:
This work was supported in part by the Foundation Fighting Blindness (grant number TA-NMT-0613-0620-UMN ); National Institutes of Health / National Eye Institute (grant numbers R01EY026012 , R01EY028554 ); Office of the NIH Director ( T35OD011118 to JRP); the Elaine and Robert Larson Endowed Vision Research Chair (to DAF); Lindsay Family Foundation ; an anonymous benefactor for Age-Related Macular Degeneration Research. None of the funding agencies had a role in study design, in the collection, analysis and interpretation of data, in writing the manuscript, or in the decision to submit the manuscript for publication.

Publisher Copyright:
© 2020

Keywords

  • Age-related macular degeneration
  • Mitochondrial function
  • Nicotinamide mononucleotide
  • Pyrroloquinoline quinone
  • Rapamycin
  • Retinal pigment epithelium

Fingerprint Dive into the research topics of 'Improving retinal mitochondrial function as a treatment for age-related macular degeneration'. Together they form a unique fingerprint.

Cite this