Mechanisms of protection of retinal pigment epithelial cells from oxidant injury by humanin and other mitochondrial-derived peptides: Implications for age-related macular degeneration

Redox Biol. 2020 Oct;37:101663. doi: 10.1016/j.redox.2020.101663. Epub 2020 Jul 29.


The mitochondrial-derived peptides (MDPs) are a new class of small open reading frame encoded polypeptides with pleiotropic properties. The prominent members are Humanin (HN) and small HN-like peptide (SHLP) 2, which encode 16S rRNA, while mitochondrial open reading frame of the twelve S c (MOTS-c) encodes 12S rRNA of the mitochondrial genome. While the multifunctional properties of HN and its analog 14-HNG have been well documented, their protective role in the retinal pigment epithelium (RPE)/retina has been investigated only recently. In this review, we have summarized the multiple effects of HN and its analogs, SHLP2 and MOTS-c in oxidatively stressed human RPE and the regulatory pathways of signaling, mitochondrial function, senescence, and inter-organelle crosstalk. Emphasis is given to the mitochondrial functions such as biogenesis, bioenergetics, and autophagy in RPE undergoing oxidative stress. Further, the potential use of HN and its analogs in the prevention of age-related macular degeneration (AMD) are also presented. In addition, the role of novel, long-acting HN elastin-like polypeptides in nanotherapy of AMD and other ocular diseases stemming from oxidative damage is discussed. It is expected MDPs will become a promising group of mitochondrial peptides with valuable therapeutic applications in the treatment of retinal diseases.

Keywords: Mitochondria-derived peptides; Mitochondrial function; Nano delivery; Oxidative stress; Retinal pigment epithelium; Signal mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Caenorhabditis elegans
  • Endothelial Cells
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins* / pharmacology
  • Macular Degeneration* / drug therapy
  • Macular Degeneration* / genetics
  • Metal Nanoparticles*
  • Mice
  • Mice, Inbred NOD
  • Mitochondria / drug effects
  • Neurons
  • Oxidants / pharmacology
  • Peptides
  • RNA, Ribosomal, 16S
  • Retinal Pigments* / pharmacology
  • Silver


  • Intracellular Signaling Peptides and Proteins
  • Oxidants
  • Peptides
  • RNA, Ribosomal, 16S
  • Retinal Pigments
  • humanin
  • Silver