Mol Neurobiol. 2021 Nov 19; doi: 10.1007/s12035-021-02630-4. Epub 2021 Nov 19.

Carbon Monoxide-Neuroglobin Axis Targeting Metabolism Against Inflammation in BV-2 Microglial Cells.

Molecular neurobiology

Daniela Dias-Pedroso, José S Ramalho, Vilma A Sardão, John G Jones, Carlos C Romão, Paulo J Oliveira, Helena L A Vieira

PMID: 34797521 DOI: 10.1007/s12035-021-02630-4

Abstract

Microglia are the immune competent cell of the central nervous system (CNS), promoting brain homeostasis and regulating inflammatory response against infection and injury. Chronic or exacerbated neuroinflammation is a cause of damage in several brain pathologies. Endogenous carbon monoxide (CO), produced from the degradation of heme, is described as anti-apoptotic and anti-inflammatory in several contexts, including in the CNS. Neuroglobin (Ngb) is a haemoglobin-homologous protein, which upregulation triggers antioxidant defence and prevents neuronal apoptosis. Thus, we hypothesised a crosstalk between CO and Ngb, in particular, that the anti-neuroinflammatory role of CO in microglia depends on Ngb. A novel CO-releasing molecule (ALF826) based on molybdenum was used for delivering CO in microglial culture.BV-2 mouse microglial cell line was challenged with lipopolysaccharide (LPS) for triggering inflammation, and after 6 h ALF826 was added. CO exposure limited inflammation by decreasing inducible nitric oxide synthase (iNOS) expression and the production of nitric oxide (NO) and tumour necrosis factor-α (TNF-α), and by increasing interleukine-10 (IL-10) release. CO-induced Ngb upregulation correlated in time with CO's anti-inflammatory effect. Moreover, knocking down Ngb reversed the anti-inflammatory effect of CO, suggesting that dependents on Ngb expression. CO-induced Ngb upregulation was independent on ROS signalling, but partially dependent on the transcriptional factor SP1. Finally, microglial cell metabolism is also involved in the inflammatory response. In fact, LPS treatment decreased oxygen consumption in microglia, indicating a switch to glycolysis, which is associated with a proinflammatory. While CO treatment increased oxygen consumption, reverting LPS effect and indicating a metabolic shift into a more oxidative metabolism. Moreover, in the absence of Ngb, this phenotype was no longer observed, indicating Ngb is needed for CO's modulation of microglial metabolism. Finally, the metabolic shift induced by CO did not depend on alteration of mitochondrial population. In conclusion, neuroglobin emerges for the first time as a key player for CO signalling against exacerbated inflammation in microglia.

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords: Carbon monoxide; Cell metabolism; Microglia; Neuroglobin; Neuroinflammation; Oxidative phosphorylation

References

1. Kaminska B, Mota M, Pizzi M (2016) Signal transduction and epigenetic mechanisms in the control of microglia activation during neuroinflammation. Biochim Biophys Acta - Mol Basis Dis 1862:339–351. https://doi.org/10.1016/j.bbadis.2015.10.026 - PubMed
2. Glass CK, Saijo K, Winner B et al (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934. https://doi.org/10.1016/j.cell.2010.02.016 - PubMed
3. Dokalis N, Prinz M (2019) Resolution of neuroinflammation: Mechanisms and potential therapeutic option. Semin Immunopathol 41:699–709. https://doi.org/10.1007/s00281-019-00764-1 - PubMed
4. Zheng D, Liwinski T, Elinav E (2020) Inflammasome activation and regulation: Toward a better understanding of complex mechanisms. Cell Discov 6:36. https://doi.org/10.1038/s41421-020-0167-x - PubMed
5. Li J, Baud O, Vartanian T et al (2005) Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. PNAS 102:9936–9941 - PubMed
6. Ni J, Wu Z, Stoka V et al (2019) Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice. Aging Cell 18:e12856. https://doi.org/10.1111/acel.12856 - PubMed
7. Mckenzie BA, Mamik MK, Saito LB et al (2019) Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis. PNAS 116:E6065–E6074. https://doi.org/10.1073/pnas.1909025116 - PubMed
8. Voloboueva LA, Emery JF, Sun X, Giffard RG (2013) Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin. FEBS Lett 587:756–762. https://doi.org/10.1016/j.febslet.2013.01.067 - PubMed
9. Nareika A, He L, Game BA et al (2005) Sodium lactate increases LPS-stimulated MMP and cytokine expression in U937 histiocytes by enhancing AP-1 and NF-κB transcriptional activities. Am J Physiol - Endocrinol Metab 289:534–542. https://doi.org/10.1152/ajpendo.00462.2004 - PubMed
10. Gimeno-Bayón J, López-López A, Rodríguez MJ, Mahy N (2014) Glucose pathways adaptation supports acquisition of activated microglia phenotype. J Neurosci Res 92:723–731. https://doi.org/10.1002/jnr.23356 - PubMed
11. Nair S, Sobotka KS, Joshi P et al (2019) Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo. Glia 67:1047–1061. https://doi.org/10.1002/glia.23587 - PubMed
12. Shen Y, Kapfhamer D, Minnella AM et al (2017) Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP. Nat Commun 8:624. https://doi.org/10.1038/s41467-017-00707-0 - PubMed
13. Louveau A, the C/ CCP with C-IDMT a RP and PAO, Nerrière-Daguin V, Vanhove B et al (2015) Targeting the CD80 / CD86 costimulatory pathway with CTLA4-Ig directs microglia toward a repair phenotype and promotes axonal outgrowth. Glia 63:2298–2312. https://doi.org/10.1002/glia.22894 - PubMed
14. Bramlett HM, Dietrich WD (2004) Pathophysiology of cerebral ischemia and brain trauma: Similarities and differences. J Cereb Blood Flow Metab 24:133–150. https://doi.org/10.1097/01.WCB.0000111614.19196.04 - PubMed
15. Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci 61:748–755. https://doi.org/10.1073/pnas.61.2.748 - PubMed
16. Motterlini R, Foresti R (2014) Heme oxygenase-1 as a target for drug discovery. Antioxid Redox Signal 20:1810–1826. https://doi.org/10.1089/ars.2013.5658 - PubMed
17. Queiroga CSF, Vercelli A, Vieira HLA (2015) Carbon monoxide and the CNS: Challenges and achievements. Br J Pharmacol 172:1533–1545. https://doi.org/10.1111/bph.12729 - PubMed
18. Hanafy KA, Oh J, Otterbein LE (2013) Carbon monoxide and the brain: Time to rethink the dogma. Curr Pharm Des 19:2771–2775 - PubMed
19. Bilban M, Haschemi A, Wegiel B et al (2008) Heme oxygenase and carbon monoxide initiate homeostatic signaling. J Mol Med 86:267–279. https://doi.org/10.1007/s00109-007-0276-0 - PubMed
20. Vieira HLA, Queiroga CSF, Alves PM (2008) Pre-conditioning induced by carbon monoxide provides neuronal protection against apoptosis. J Neurochem 107:375–384. https://doi.org/10.1111/j.1471-4159.2008.05610.x - PubMed
21. Queiroga CSF, Almeida AS, Martel C et al (2010) Glutathionylation of adenine nucleotide translocase induced by carbon monoxide prevents mitochondrial membrane permeabilization and apoptosis. J Biol Chem 285:17077–17088. https://doi.org/10.1074/jbc.M109.065052 - PubMed
22. Almeida AS, Queiroga CSF, Sousa MFQ et al (2012) Carbon monoxide modulates apoptosis by reinforcing oxidative metabolism in astrocytes: Role of Bcl-2. J Biol Chem 287:10761–10770. https://doi.org/10.1074/jbc.M111.306738 - PubMed
23. Lavitrano M, Smolenski RT, Musumeci A et al (2004) Carbon monoxide improves cardiac energetics and safeguards the heart during reperfusion after cardiopulmonary bypass in pigs. FASEB J 18:1093–1095. https://doi.org/10.1096/fj.03-0996fje - PubMed
24. Upadhyay KK, Jadeja RN, Vyas HS et al (2020) Carbon monoxide releasing molecule-A1 improves nonalcoholic steatohepatitis via Nrf2 activation mediated improvement in oxidative stress and mitochondrial function. Redox Biol 28:101314. https://doi.org/10.1016/j.redox.2019.101314 - PubMed
25. Wegiel B, Gallo D, Csizmadia E et al (2013) Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth. Cancer Res 73:7009–7021. https://doi.org/10.1158/0008-5472.CAN-13-1075 - PubMed
26. Almeida AS, Soares NL, Sequeira CO et al (2018) Improvement of neuronal differentiation by carbon monoxide: Role of pentose phosphate pathway. Redox Biol 17:338–347. https://doi.org/10.1016/j.redox.2018.05.004 - PubMed
27. Zeynalov E, Dore S (2009) Low doses of carbon monoxide protect against experimental focal brain ischemia. Neurotox Res 15:133–137. https://doi.org/10.1007/s12640-009-9014-4 - PubMed
28. Wang B, Cao W, Biswal S, Doré S (2011) Carbon monoxide-activated Nrf2 pathway leads to protection against permanent focal cerebral ischemia. Stroke 42:2605–2610. https://doi.org/10.1161/STROKEAHA.110.607101 - PubMed
29. El Ali Z, Ollivier A, Manin S et al (2020) Therapeutic effects of CO-releaser/Nrf2 activator hybrids (HYCOs) in the treatment of skin wound, psoriasis and multiple sclerosis. Redox Biol 34:101521. https://doi.org/10.1016/j.redox.2020.101521 - PubMed
30. Chora ÂA, Fontoura P, Cunha A et al (2007) Heme oxygenase – 1 and carbon monoxide suppress autoimmune neuroinflammation. J Clin Invest 117:438–447. https://doi.org/10.1172/JCI28844DS1 - PubMed
31. Bani-Hani MG, Greenstein D, Mann BE et al (2006) Modulation of thrombin-induced neuroinflammation in BV-2 microglia by carbon monoxide-releasing molecule 3. J Pharmacol Exp Ther 318:1315–1322. https://doi.org/10.1124/jpet.106.104729 - PubMed
32. Wang J, Zhang D, Fu X et al (2018) Carbon monoxide-releasing molecule-3 protects against ischemic stroke by suppressing neuroinflammation and alleviating blood-brain barrier disruption. J Neuroinflammation 15:188. https://doi.org/10.1186/s12974-018-1226-1 - PubMed
33. Hervera A, Leánez S, Negrete R et al (2012) Carbon monoxide reduces neuropathic pain and spinal microglial activation by inhibiting nitric oxide synthesis in mice. PLoS One 7:1–10. https://doi.org/10.1371/journal.pone.0043693 - PubMed
34. Zuckerbraun BS, Chin BY, Bilban M et al (2007) Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J 21:1099–1106. https://doi.org/10.1096/fj.06-6644com - PubMed
35. Bilban M, Bach FH, Otterbein SL et al (2006) Carbon monoxide orchestrates a protective response through PPARγ. Immunity 24:601–610. https://doi.org/10.1016/j.immuni.2006.03.012 - PubMed
36. Kim HS, Loughran PA, Rao J et al (2008) Carbon monoxide activates NF- B via ROS generation and Akt pathways to protect against cell death of hepatocytes. Am J Physiol Gastrointest Liver Physiol 295:146–152. https://doi.org/10.1152/ajpgi.00105.2007 - PubMed
37. Lee SJ, Ryter SW, Xu JF et al (2011) Carbon monoxide activates autophagy via mitochondrial reactive oxygen species formation. Am J Respir Cell Mol Biol 45:867–873 - PubMed
38. Kim HJ, Joe Y, Rah S-Y et al (2018) Carbon monoxide-induced TFEB nuclear translocation enhances mitophagy/mitochondrial biogenesis in hepatocytes and ameliorates inflammatory liver injury. Cell Death Dis 9:1060. https://doi.org/10.1038/s41419-018-1112-x - PubMed
39. Lee DW, Young SH, Jeong JH et al (2017) Carbon monoxide regulates glycolysis-dependent NLRP3 inflammasome activation in macrophages. Biochem Biophys Res Commun 493:957–963. https://doi.org/10.1016/j.bbrc.2017.09.111 - PubMed
40. Suliman HB, Carraway MS, Tatro LG, Piantadosi C a (2007) A new activating role for CO in cardiac mitochondrial biogenesis. J Cell Sci 120:299–308 . doi: https://doi.org/10.1242/jcs.03318 - PubMed
41. Rhodes MA, Carraway MS, Piantadosi CA et al (2009) Carbon monoxide, skeletal muscle oxidative stress, and mitochondrial biogenesis in humans. Am J Physiol Circ Physiol 297:H392–H399. https://doi.org/10.1152/ajpheart.00164.2009 - PubMed
42. Pecorella SRH, Potter JVF, Cherry AD et al (2015) The HO-1 / CO system regulates mitochondrial-capillary density relationships in human skeletal muscle. Am J Physiol Lung Cell Mol Physiol 309:L857–L871. https://doi.org/10.1152/ajplung.00104.2015 - PubMed
43. Romão CC, Vieira HLA (2015) Metal carbonyl prodrugs: CO delivery and beyond. Wiley-VCH - PubMed
44. Burmester T, Weich B, Reinhardt S, Hankeln T (2000) A vertebrate globin expressed in the brain. Nature 407:520–523. https://doi.org/10.1038/35035093 - PubMed
45. De Marinis E, Acaz-Fonseca E, Arevalo MA et al (2013) 17β-Oestradiol anti-inflammatory effects in primary astrocytes require oestrogen receptor β-mediated neuroglobin up-regulation. J Neuroendocrinol 25:260–270. https://doi.org/10.1111/jne.12007 - PubMed
46. Li W-D, Sun Q, Zhang X-S et al (2014) Expression and cell distribution of neuroglobin in the brain tissue after experimental subarachnoid hemorrhage in rats: A pilot study. Cell Mol Neurobiol 34:247–255. https://doi.org/10.1007/s10571-013-0008-7 - PubMed
47. Acaz-Fonseca E, Duran JC, Carrero P et al (2015) Sex differences in glia reactivity after cortical brain injury. Glia 63:1966–1981. https://doi.org/10.1002/glia.22867 - PubMed
48. Amri F, Ghouili I, Amri M et al (2017) Neuroglobin protects astroglial cells from hydrogen peroxide-induced oxidative stress and apoptotic cell death. J Neurochem 140:151–169. https://doi.org/10.1111/jnc.13876 - PubMed
49. Liu J, Yu Z, Guo S et al (2009) Effects of neuroglobin overexpression on mitochondrial function and oxidative stress following hypoxia/reoxygenation in cultured neurons. J Neurosci Res 87:164–170. https://doi.org/10.1002/jnr.21826 - PubMed
50. Sun Y, Jin K, Mao XO et al (2001) Neuroglobin is up-regulated by and protects neurons from hypoxic-ischemic injury. PNAS 98:15306–15311. https://doi.org/10.1073/pnas.251466698 - PubMed
51. Avila-Rodriguez M, Garcia-Segura LM, Hidalgo-lanussa O et al (2016) Tibolone protects astrocytic cells from glucose deprivation through a mechanism involving estrogen receptor beta and the upregulation of neuroglobin expression. Mol Cell Endocrinol 433:35–46. https://doi.org/10.1016/j.mce.2016.05.024 - PubMed
52. Yu Z, Xu J, Liu N et al (2012) Mitochondrial distribution of neuroglobin and its response to oxygen-glucose deprivation in primary-cultured mouse cortical neurons. Neuroscience 218:235–242. https://doi.org/10.1016/j.neuroscience.2012.05.054 - PubMed
53. Yu Z, Liu N, Li Y et al (2013) Neuroglobin overexpression inhibits oxygen–glucose deprivation-induced mitochondrial permeability transition pore opening in primary cultured mouse cortical neurons. Neurobiol Dis 56:95–103. https://doi.org/10.1016/j.nbd.2013.04.015 - PubMed
54. Wei X, Yu Z, Cho K-S et al (2011) Neuroglobin is an endogenous neuroprotectant for retinal ganglion cells against glaucomatous damage. Am J Pathol 179:2788–2797. https://doi.org/10.1016/j.ajpath.2011.08.015 - PubMed
55. Singh S, Zhuo M, Gorgun FM, Englander EW (2013) Overexpressed neuroglobin raises threshold for nitric oxide-induced impairment of mitochondrial respiratory activities and stress signaling in primary cortical neurons. Nitric Oxide 32:21–28. https://doi.org/10.1016/j.niox.2013.03.008 - PubMed
56. Cai B, Li W, Mao XO et al (2016) Neuroglobin overexpression inhibits AMPK signaling and promotes cell anabolism. Mol Neurobiol 53:1254–1265. https://doi.org/10.1007/s12035-014-9077-y - PubMed
57. Yu Z, Zhang Y, Liu N et al (2016) Roles of neuroglobin binding to mitochondrial complex III subunit cytochrome c1 in oxygen-glucose deprivation-induced neurotoxicity in primary neurons. Mol Neurobiol 53:3249–3257. https://doi.org/10.1007/s12035-015-9273-4 - PubMed
58. Khan AA, Wang Y, Sun Y et al (2006) Neuroglobin-overexpressing transgenic mice are resistant to cerebral and myocardial ischemia. Proc Natl Acad Sci 103:17944–17948. https://doi.org/10.1073/pnas.0607497103 - PubMed
59. Ren C, Wang P, Wang B et al (2015) Limb remote ischemic per-conditioning in combination with post-conditioning reduces brain damage and promotes neuroglobin expression in the rat brain after ischemic stroke. Restor Neurol Neurosci 33:369–379. https://doi.org/10.3233/RNN-140413 - PubMed
60. Hidalgo-Lanussa O, Ávila-Rodriguez M, Baez-Jurado E et al (2018) Tibolone reduces oxidative damage and inflammation in microglia stimulated with palmitic acid through mechanisms involving estrogen receptor beta. Mol Neurobiol 55:5462–5477. https://doi.org/10.1007/s12035-017-0777-y - PubMed
61. Zhang L-N, Ai Y-H, Gong H et al (2014) Expression and role of neuroglobin in rats with sepsis-associated encephalopathy. Crit Care Med 42:e12–e21. https://doi.org/10.1097/CCM.0b013e3182a63b1a - PubMed
62. Tun SBB, Barathi VA, Luu CD et al (2019) Effects of exogenous neuroglobin (Ngb) on retinal inflammatory chemokines and microglia in a rat model of transient hypoxia. Sci Rep 9:3–9. https://doi.org/10.1038/s41598-019-55315-3 - PubMed
63. Liu N, Yu Z, Xiang S et al (2012) Transcriptional regulation mechanisms of hypoxia-induced neuroglobin gene expression. Biochem J 443:153–164. https://doi.org/10.1042/BJ20111856 - PubMed
64. Chi P-L, Lin C-C, Chen Y-W et al (2014) CO induces Nrf2-dependent heme oxygenase-1 transcription by cooperating with Sp1 and c-Jun in rat brain astrocytes. Mol Neurobiol. https://doi.org/10.1007/s12035-014-8869-4 - PubMed
65. Motterlini R, Sawle P, Hammad J et al (2005) CORM-A1: A new pharmacologically active carbon monoxide-releasing molecule. FASEB J 19:284–286. https://doi.org/10.1096/fj.04-2169fje - PubMed
66. Schindelin J, Arganda-Carreras I, Frise E et al (2012) Fiji: An open-source platform for biological-image analysis. Nat Methods 9:676–682. https://doi.org/10.1038/nmeth.2019 - PubMed
67. Green MR, Sambrook J (2017) Isolation of High-Molecular-Weight DNA Using Organic Solvents. Cold Spring Harb Protoc 2017:pdb.prot093450 . doi: https://doi.org/10.1101/pdb.prot093450 - PubMed
68. Ji X, Damera K, Zheng Y et al (2016) Toward carbon monoxide-based therapeutics: Critical drug delivery and developability issues. J Pharm Sci 105:406–416. https://doi.org/10.1016/j.xphs.2015.10.018 - PubMed
69. Otterbein LE, Bach FH, Alam J et al (2000) Carbon monoxide has anti-inflammatory effects involving the mitogen- activated protein kinase pathway. Nat Med 6:422–428. https://doi.org/10.1038/74680 - PubMed
70. Morse D, Pischke SE, Zhou Z et al (2003) Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1. J Biol Chem 278:36993–36998. https://doi.org/10.1074/jbc.M302942200 - PubMed
71. Nakahira K, Hong PK, Xue HG et al (2006) Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts. J Exp Med 203:2377–2389. https://doi.org/10.1084/jem.20060845 - PubMed
72. Kim S-K, Joe Y, Chen Y et al (2017) Carbon monoxide decreases interleukin-1β levels in the lung through the induction of pyrin. Cell Mol Immunol 14:349–359. https://doi.org/10.1038/cmi.2015.79 - PubMed
73. Beishline K, Azizkhan-Clifford J (2015) Sp1 and the ‘hallmarks of cancer.’ FEBS J 282:224–258 . doi: https://doi.org/10.1111/febs.13148 - PubMed
74. Chien PT-Y, Lin C-C, Hsiao L-D, Yang C-M (2015) Induction of HO-1 by carbon monoxide releasing molecule-2 attenuates thrombin-induced COX-2 expression and hypertrophy in primary human cardiomyocytes. Toxicol Appl Pharmacol 289:349–359. https://doi.org/10.1016/j.taap.2015.09.009 - PubMed
75. Lin HH, Lai SC, Chau LY (2011) Heme oxygenase-1/carbon monoxide induces vascular endothelial growth factor expression via p38 kinase-dependent activation of Sp1. J Biol Chem 286:3829–3838. https://doi.org/10.1074/jbc.M110.168831 - PubMed
76. Zhang W, Tian Z, Sha S et al (2011) Functional and sequence analysis of human neuroglobin gene promoter region. Biochim Biophys Acta - Gene Regul Mech 1809:236–244. https://doi.org/10.1016/j.bbagrm.2011.02.003 - PubMed
77. Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K et al (2007) UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446:1091–1095. https://doi.org/10.1038/nature05704 - PubMed
78. Stence N, Waite M, Dailey ME (2001) Dynamics of microglial activation: A confocal time-lapse analysis in hippocampal slices. Glia 33:256–266 - PubMed
79. Schafer DP, Lehrman EK, Kautzman AG et al (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. https://doi.org/10.1016/j.neuron.2012.03.026 - PubMed
80. Ghosh S, Castillo E, Frias ES, Swanson RA (2018) Bioenergetic regulation of microglia. Glia 66:1200–1212. https://doi.org/10.1002/glia.23271 - PubMed
81. Wilson JLJL, Bouillaud F, Almeida ASAS et al (2017) Carbon monoxide reverses the metabolic adaptation of microglia cells to an inflammatory stimulus. Free Radic Biol Med 104:311–323. https://doi.org/10.1016/j.freeradbiomed.2017.01.022 - PubMed
82. Nickens KP, Wikstrom JD, Shirihai OS et al (2013) A bioenergetic profile of non-transformed fibroblasts uncovers a link between death-resistance and enhanced spare respiratory capacity. Mitochondrion 13:662–667. https://doi.org/10.1016/j.mito.2013.09.005 - PubMed
83. Choi YK, Park JH, Baek Y-Y et al (2016) Carbon monoxide stimulates astrocytic mitochondrial biogenesis via L-type calcium channel-mediated PGC-1 alpha / ERR alpha activation. Biochem Biophys Res Commun 479:297–304. https://doi.org/10.1016/j.bbrc.2016.09.063 - PubMed

Publication Types

• Journal Article

Grant support

• PTDC/MEC-NEU/28750/2017/Fundação para a Ciência e a Tecnologia
• UID/Multi/04378/2019/Fundação para a Ciência e a Tecnologia
• UID/Multi/04462/2013/Fundação para a Ciência e a Tecnologia
• PD/BD/128338/2017/Fundação para a Ciência e a Tecnologia
• IF/01182/2015/Fundação para a Ciência e a Tecnologia
• LA/P/0140/2020/Fundação para a Ciência e a Tecnologia