Erythropoietin promotes hippocampal mitochondrial function and enhances cognition in mice

Abstract

Erythropoietin (EPO) improves neuronal mitochondrial function and cognition in adults after brain injury and in those afflicted by psychiatric disorders. However, the influence of EPO on mitochondria and cognition during development remains unexplored. We previously observed that EPO stimulates hippocampal-specific neuronal maturation and synaptogenesis early in postnatal development in mice. Here we show that EPO promotes mitochondrial respiration in developing postnatal hippocampus by increasing mitochondrial content and enhancing cellular respiratory potential. Ultrastructurally, mitochondria profiles and total vesicle content were greater in presynaptic axon terminals, suggesting that EPO enhances oxidative metabolism and synaptic transmission capabilities. Behavioural tests of hippocampus-dependent memory at early adulthood, showed that EPO improves spatial and short-term memory. Collectively, we identify a role for EPO in the murine postnatal hippocampus by promoting mitochondrial function throughout early postnatal development, which corresponds to enhanced cognition by early adulthood.

Erythropoietin in Spinocerebellar Ataxia Type 2: Feasibility and Proof‐of‐Principle Issues from a Randomized Controlled Study

“…EPO is a cytokine that regulates erythropoiesis; however, several evidences show an additional role as a neurotrophic factor. EPO and its receptors are highly expressed in neurons, astrocytes, and microglia, 6 which stimulate antiapoptotic, anti‐inflammatory, antioxidative, and anticytotoxic pathways 7‐9 …”

Erythropoietin receptor regulates tumor mitochondrial biogenesis through iNOS and pAKT

“…Furthermore, EPOR and VDAC1, as a surrogate of mitochondrial content (61) correlated positively in most lung cancer types, except for large cell carcinoma. Although VDAC1 is also differentially expressed by apoptotic regulation (62), we propose that the approximately 27% (r 2 squared Pearson) of VDAC1 variation among the lung cancer biopsies, which was explained by EPOR expression, reflects differences in mitochondrial content (44,61,63,64). When we analyzed VDAC1 expression levels in different datasets of lung adenocarcinomas (37)(38)(39)(40), we observed that it is higher expressed in tumors than in healthy tissue and is associated with poor survival.…”

The Effect of Erythropoietin and Its Derivatives on Ischemic Stroke Therapy: A Comprehensive Review

“…EPO's acute and extended synaptic plasticity effects and its ability to modulate both excitatory and inhibitory neurotransmissions could partly contribute to the observed cognitive behavioral effects (Khalid et al, 2021). Further study proved that promoting mitochondrial function throughout early postnatal development also corresponded to enhanced cognition by early adulthood in mice (Jacobs et al, 2021). It was shown that EPOR exerted the central role in maturation of GABAergic interneurons in the hippocampus and EPO-driven neurogenesis (Wakhloo et al, 2020;Khalid et al, 2021).…”

“…These actions allow for cell survival, proliferation, and differentiation. Activation of the homodimeric EPOR/EPOR leads to erythropoiesis, while activation of the heterodimeric EPOR/βcR (CD131) leads to tissue repair and recovery ( Socolovsky et al, 2001 ; Tsiftsoglou, 2021 ; Maiese, 2015 ; Gyetvai et al, 2017 ; Othman et al, 2018 ; Jarero-Basulto et al, 2020 ; Peng et al, 2020 ; Jacobs et al, 2021 ; Larpthaveesarp et al, 2021 ). The JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway is involved in many vital cellular processes, including cell growth, differentiation, proliferation, and regulatory immune functions; PI3K/AKT (Phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B) is activated by numerous genes and improves cell proliferation during erythropoiesis in hypoxia; ERK/MAPK (extracellular signal-regulated kinase/Mitogen-activated protein kinase) is the key signaling pathway that regulates a wide variety of cellular processes, including proliferation, differentiation, apoptosis, and stress responses; GATA1, FOG1, TAL-1, and EKLF (Erythroid Kruppel-like Factor, also called KLF1) are master transcriptional regulators of erythropoiesis; BC11A, transcriptional repressor B-cell lymphoma/leukemia 11A, is a transcriptional repressor of erythropoiesis; TGF-β, transforming growth factor-β, regulates cell growth and differentiation, apoptosis, etc.…”