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

Abstract

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.

Deletion of Mitochondrial Translocator Protein (TSPO) Gene Decreases Oxidative Retinal Pigment Epithelial Cell Death via Modulation of TRPM2 Channel

“…The rate of oxygen consumption is high in the retina [ 1 ]. A large amount of fROS generation in the ARPE19 cells from a variety of cellular sources, including mitochondria [ 1 ].…”

“…The rate of oxygen consumption is high in the retina [ 1 ]. A large amount of fROS generation in the ARPE19 cells from a variety of cellular sources, including mitochondria [ 1 ]. The activation of TRPM2 induces overload Ca 2+ influx-mediated oxidative stress by the gating mPTP and injuring mMDP [ 9 , 18 , 19 ].…”

“…Age-related macular degeneration (AMD) disease causes blindness in old people [ 1 ]. The incidences of AMD with eleven million patients are high in the USA [ 2 ].…”

“…The dry AMD isn’t totally treated by the current drugs. However, accumulation data indicate that inhibition of excessive fROS generation in the membranes of retinal mitochondria is a reasonable way for the treatment of dry AMD disease [ 1 , 10 , 11 ].…”

Grape Seed Proanthocyanindin Extract Moderated Retinal Pigment Epithelium Cellular Senescence Through NAMPT/SIRT1/NLRP3 Pathway

“…Cellular senescence, which was an important cause of physiological and pathological changes in the ocular structure including the retina [1], was responsible for the development of diabetic retinopathy (DR), retinitis pigmentosa (RP) and age-related macular degeneration (AMD). The cellular senescence related retinal degenerative disorders would affect the visual function of more than 500 million patients, even lead to blindness in severe cases [2].…”