Heme-oxygenase I and PCG-1α regulate mitochondrial biogenesis via microglial activation of alpha7 nicotinic acetylcholine receptors using PNU282987

[Aims]: A loss in brain acetylcholine and cholinergic markers, subchronic inflammation, and impaired mitochondrial function, which lead to low-energy production and high oxidative stress, are common pathological factors in several neurodegenerative diseases (NDDs). Glial cells are important for brain homeostasis, and microglia controls the central immune response, where α7 acetylcholine nicotinic receptors (nAChR) seem to play a pivotal role; however, little is known about the effects of this receptor in metabolism. Therefore, the aim of this study was to evaluate if glial mitochondrial energetics could be regulated through α7 nAChR. [Results]: Primary glial cultures treated with the α7 nicotinic agonist PNU282987 increased their mitochondrial mass and their mitochondrial oxygen consumption without increasing oxidative stress; these changes were abolished when nuclear erythroid 2-related factor 2 (Nrf2) was absent, heme oxygenase-1 (HO-1) was inhibited, or peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) was silenced. More specifically, microglia of animals treated intraperitoneally with the α7 nAChR agonist PNU282987 (10 mg/kg) showed a significant increase in mitochondrial mass. Interestingly, LysMcre-Hmox1Δ/Δ and PGC-1α−/− animals showed lower microglial mitochondrial levels and treatment with PNU282987 did not produce effects on mitochondrial levels.[Innovation]: Increases in microglial mitochondrial mass and metabolism can be achieved via α7 nAChR by a mechanism that implicates Nrf2, HO-1, and PGC-1α. This signaling pathway could open a new strategy for the treatment of NDDs, such as Alzheimer's, characterized by a reduction of cholinergic markers. [Conclusion]: α7 nAChR signaling increases glial mitochondrial mass, both in vitro and in vivo, via HO-1 and PCG-1α. These effects could be of potential benefit in the context of NDDs.This work was supported by the Spanish Ministry of Economy and Competence Ref. SAF2012-23332 and SAF2015-63935-R to M.G.L.; Ref. SAF2012-37693 to M.M. Comunidad Autónoma de Madrid grant number S2010/BMD-2361 to M.M. E.N. a predoctoral fellowship from Universidad Autónoma de Madrid. The work in SC laboratory is supported by grants from the Instituto de Salud Carlos III FIS (PI12/00933 and PI15/00448) and by Comunidad de Madrid (S2011/BMD-2402). We also thank the Fundación Teófilo Hernando, the Network of Excellence Nrf2-net of MINECO, and the European Cooperation and Technology (COST Action BM1203/EU-ROS).Peer reviewe