Protective Mechanisms of the Mitochondrial‐Derived Peptide Humanin in Oxidative and Endoplasmic Reticulum Stress in RPE Cells

Abstract

Age-related macular degeneration (AMD) is the leading cause of severe and irreversible vision loss and is characterized by progressive degeneration of the retina resulting in loss of central vision. The retinal pigment epithelium (RPE) is a critical site of pathology of AMD. Mitochondria and the endoplasmic reticulum which lie in close anatomic proximity to each other are targets of oxidative stress and endoplasmic reticulum (ER) stress, respectively, and contribute to the progression of AMD. The two organelles exhibit close interactive function via various signaling mechanisms. Evidence for ER-mitochondrial crosstalk in RPE under ER stress and signaling pathways of apoptotic cell death is presented. The role of humanin (HN), a prominent member of a newly discovered family of mitochondrial-derived peptides (MDPs) expressed from an open reading frame of mitochondrial 16S rRNA, in modulation of ER and oxidative stress in RPE is discussed. HN protected RPE cells from oxidative and ER stress-induced cell death by upregulation of mitochondrial GSH, inhibition of ROS generation, and caspase 3 and 4 activation. The underlying mechanisms of ER-mitochondrial crosstalk and modulation by exogenous HN are discussed. The therapeutic use of HN and related MDPs could potentially prove to be a valuable approach for treatment of AMD.

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

“…The involvement of the ERS has been increasingly recognized as a contributor in a variety of diseases, including glaucoma [52], DR [53], AMD [54] and RP [55]. GRP78, a protein chaperone, was chosen as the ERS marker in the present experiment [56].…”

BMSCs protect against renal ischemia‐reperfusion injury by secreting exosomes loaded with miR‐199a‐5p that target BIP to inhibit endoplasmic reticulum stress at the very early reperfusion stages

“…Increasing evidence strongly suggests that ER stress could be an underlying mechanism for disease therapies and homeostatic regulation under stress, including I/R injury. Notably, ER stress has been reported to play dual roles under stress depending on the severity and duration of stress, and extremely strong stress has been found to lead to ER stress, accelerating cell death (18, 41–43). Using renal I/R models, we demonstrated that increasing ER stress resulted in more apoptosis and damage; the suppression of ER stress amplified the BMSC‐induced protection against renal I/R injury.…”

Humanin levels in human seminal plasma and spermatozoa are related to sperm quality

“…It is well established that reactive oxygen species (ROS), which are mainly generated in the mitochondrial respiratory chain, impair sperm production, motility, membrane, and DNA integrity and also influence sperm capacitation (Christova et al ., ; Henkel et al ., ; Brouwers et al ., ; Aitken et al ., ; Lee et al ., ). Humanin has been reported to prevent ROS accumulating in cardiomyocytes (Blasco et al ., ), cortical neurons (Cui et al ., ), retinal pigment epithelium (Minasyan et al ., ), and rat pancreatic beta cells (Paharkova et al ., ), etc. Pre‐treatment with humanin analog can exert cardiologically protective effects against myocardial ischemia and reperfusion injury in mouse models (Muzumdar et al ., ).…”

“…Humanin is a mitochondrial‐derived 24‐amino‐acid peptide encoded in the mitochondrial genome by the 16S ribosomal RNA gene MT‐RNR2 (Hashimoto et al ., ). Evidence suggests that humanin is secreted and expressed in multiple tissues including the brain (Hashimoto et al ., ; Matsuoka, ), retinal pigment epithelium (Minasyan et al ., ; Nashine et al ., ), blood vessels (Bachar et al ., ; Muzumdar et al ., ), pancreatic beta cells (Hoang et al ., ), tumors (Gottardo et al ., ; Omar et al ., ), and testes (Colon et al ., ; Lue et al ., ), and is also present in serum (Widmer et al ., ; Lee et al ., ; Yen et al ., ). Humanin has been demonstrated to have neuroprotective, anti‐inflammatory, antiapoptotic, antiaging, and antifibrilogenic properties through interaction with a series of targets including BAX (Guo et al ., ; Luciano et al ., ; Zhai et al ., ), insulin‐like growth factor binding protein 3 (IGFBP3) (Ikonen et al ., ), and a tripartite receptor composed of gp130, WSX1, and CNTFR (Hashimoto et al ., ).…”