The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus

Abstract

Humanin is a small secreted peptide that is encoded in the mitochondrial genome. Humanin and its analogues have a protective role in multiple age-related diseases including type 2 diabetes and Alzheimer's disease, through cytoprotective and neuroprotective effects both in vitro and in vivo. However, the humanin-mediated signaling pathways are not well understood. In this paper, we demonstrate that humanin acts through the GP130/IL6ST receptor complex to activate AKT, ERK1/2, and STAT3 signaling pathways. Humanin treatment increases phosphorylation in AKT, ERK 1/2, and STAT3 where PI3K, MEK, and JAK are involved in the activation of those three signaling pathways, respectively. Furthermore, old mice, but not young mice, injected with humanin showed an increase in phosphorylation in AKT and ERK1/2 in the hippocampus. These findings uncover a key signaling pathway of humanin that is important for humanin's function and also demonstrates an age-specific in vivo effect in a region of the brain that is critical for memory formation in an age-dependent manner.

Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway

“…However, physiological plasma level of humanin markedly decreases with age, which likely results in the limited role in anti-apoptosis in diseases that frequently occur in elderly people, such as stroke (11). HNG, that may be synthesized artificially, has 1,000-fold stronger biological activity than humanin, thus it is referred to as a potent humanin analogue (24).…”

“…The Jak2/Stat3 cascade has been documented to be regulated by the PI3K/AKT pathway, mediating the functions in regulation of cell proliferation, anti-apoptosis and anti-senescence, cancer generation and migration, tissue development and memory formation (15)(16)(17). A study indicated that phosphorylation levels of AKT and Stat3 are increased after humanin acts on the GP130/IL6ST receptor complex (11). Activated AKT and Stat3 participate in cytoprotective and neuroprotective mechanisms of humanin in multiple age-related diseases (11).…”

“…A study indicated that phosphorylation levels of AKT and Stat3 are increased after humanin acts on the GP130/IL6ST receptor complex (11). Activated AKT and Stat3 participate in cytoprotective and neuroprotective mechanisms of humanin in multiple age-related diseases (11). Based on these data, it is reasonable to hypothesize that the PI3K/AKT pathway participates in the regulation of HNG on Jak2/Stat3 signaling.…”

“…These data raised the hypothesis that humanin may have neuroprotective functions counteracting adverse effects induced by ischemia/reperfusion. However, humanin, which is secreted from cells, decreases with age in human plasma levels, while stroke incidence notably increases with age and culminates in elderly individuals (11). This may lead to limited protection by humanin at physiological levels from stroke in the elderly, even though humanin may have the ability to counteract stroke impairment.…”

Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment

“…Humanin (HN) is a 24 aa peptide that was originally discovered as a neuroprotective factor (17), having multiple modes of action in different cell types (18). For instance, HN has been reported to be a key regulator of peripheral insulin action (19).…”