MTOR/α-ketoglutarate-mediated Signaling Pathways in the Context of Brain Neurodegeneration and Neuroprotection

Overview

Journal BBA Adv

Specialty Biochemistry

Date 2023 Apr 21

PMID 37082603

Authors

Olha Kostiuchenko

Iryna Lushnikova

Magdalena Kowalczyk

Galyna Skibo

Affiliations

Soon will be listed here.

Abstract

Cerebral disorders are largely associated with impaired cellular metabolism, despite the regulatory mechanisms designed to ensure cell viability and adequate brain function. Mechanistic target of rapamycin (mTOR) signaling is one of the most crucial factors in the regulation of energy homeostasis and its imbalance is linked with a variety of neurodegenerative diseases. Recent advances in the metabolic pathways' modulation indicate the role of α-ketoglutarate (AKG) as a major signaling hub, additionally highlighting its anti-aging and neuroprotective properties, but the mechanisms of its action are not entirely clear. In this review, we analyzed the physiological and pathophysiological aspects of mTOR in the brain. We also discussed AKG's multifunctional properties, as well as mTOR/AKG-mediated functional communications in cellular metabolism. Thus, this article provides a broad overview of the mTOR/AKG-mediated signaling pathways, in the context of neurodegeneration and endogenous neuroprotection, with the aim to find novel therapeutic strategies.

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References

Satpute R, Lomash V, Kaushal M, Bhattacharya R . Neuroprotective effects of α-ketoglutarate and ethyl pyruvate against motor dysfunction and oxidative changes caused by repeated 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine exposure in mice. Hum Exp Toxicol. 2013; 32(7):747-58. DOI: 10.1177/0960327112468172. View

Gyanwali B, Lim Z, Soh J, Lim C, Guan S, Goh J . Alpha-Ketoglutarate dietary supplementation to improve health in humans. Trends Endocrinol Metab. 2021; 33(2):136-146. DOI: 10.1016/j.tem.2021.11.003. View

Bhattacharya R, Lakshmana Rao P, Vijayaraghavan R . In vitro and in vivo attenuation of experimental cyanide poisoning by alpha-ketoglutarate. Toxicol Lett. 2002; 128(1-3):185-95. DOI: 10.1016/s0378-4274(02)00012-7. View

Fakih W, Zeitoun R, AlZaim I, Eid A, Kobeissy F, Abd-Elrahman K . Early metabolic impairment as a contributor to neurodegenerative disease: Mechanisms and potential pharmacological intervention. Obesity (Silver Spring). 2022; 30(5):982-993. DOI: 10.1002/oby.23400. View

Kuo C, Cheng C, Hou P, Lin Y, Ma H, Chung Y . HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity. Oncotarget. 2016; 7(23):34052-69. PMC: 5085137. DOI: 10.18632/oncotarget.8570. View

Kapogiannis D . Energy metabolism and the brain: a bidirectional relationship. Ageing Res Rev. 2015; 20:35-6. PMC: 5456290. DOI: 10.1016/j.arr.2015.02.002. View

Chin R, Fu X, Pai M, Vergnes L, Hwang H, Deng G . The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014; 510(7505):397-401. PMC: 4263271. DOI: 10.1038/nature13264. View

Yang H, Rudge D, Koos J, Vaidialingam B, Yang H, Pavletich N . mTOR kinase structure, mechanism and regulation. Nature. 2013; 497(7448):217-23. PMC: 4512754. DOI: 10.1038/nature12122. View

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

10.

Liu S, He L, Yao K . The Antioxidative Function of Alpha-Ketoglutarate and Its Applications. Biomed Res Int. 2018; 2018:3408467. PMC: 5884300. DOI: 10.1155/2018/3408467. View

11.

Wu M, Zhang H, Kai J, Zhu F, Dong J, Xu Z . Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats. Ann Clin Transl Neurol. 2018; 5(2):138-146. PMC: 5817831. DOI: 10.1002/acn3.507. View

12.

Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E . Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One. 2010; 5(2):e9313. PMC: 2824828. DOI: 10.1371/journal.pone.0009313. View

13.

Li D, Wang C, Yao Y, Chen L, Liu G, Zhang R . mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type. FASEB J. 2016; 30(10):3388-3399. DOI: 10.1096/fj.201600495R. View

14.

Ugur B, Bao H, Stawarski M, Duraine L, Zuo Z, Lin Y . The Krebs Cycle Enzyme Isocitrate Dehydrogenase 3A Couples Mitochondrial Metabolism to Synaptic Transmission. Cell Rep. 2017; 21(13):3794-3806. PMC: 5747319. DOI: 10.1016/j.celrep.2017.12.005. View

15.

Shen X, Wu S, Zhang J, Li M, Xu F, Wang A . Wild‑type IDH1 affects cell migration by modulating the PI3K/AKT/mTOR pathway in primary glioblastoma cells. Mol Med Rep. 2020; 22(3):1949-1957. PMC: 7411459. DOI: 10.3892/mmr.2020.11250. View

16.

Hinca S, Salcedo C, Wagner A, Goldeman C, Sadat E, Aibar M . Brain endothelial cells metabolize glutamate via glutamate dehydrogenase to replenish TCA-intermediates and produce ATP under hypoglycemic conditions. J Neurochem. 2020; 157(6):1861-1875. DOI: 10.1111/jnc.15207. View

17.

Switon K, Kotulska K, Janusz-Kaminska A, Zmorzynska J, Jaworski J . Molecular neurobiology of mTOR. Neuroscience. 2016; 341:112-153. DOI: 10.1016/j.neuroscience.2016.11.017. View

18.

Villa-Gonzalez M, Martin-Lopez G, Perez-Alvarez M . Dysregulation of mTOR Signaling after Brain Ischemia. Int J Mol Sci. 2022; 23(5). PMC: 8911477. DOI: 10.3390/ijms23052814. View

19.

van Dam T, Zwartkruis F, Bos J, Snel B . Evolution of the TOR pathway. J Mol Evol. 2011; 73(3-4):209-20. PMC: 3236823. DOI: 10.1007/s00239-011-9469-9. View

20.

Datta A, Sarmah D, Mounica L, Kaur H, Kesharwani R, Verma G . Cell Death Pathways in Ischemic Stroke and Targeted Pharmacotherapy. Transl Stroke Res. 2020; 11(6):1185-1202. DOI: 10.1007/s12975-020-00806-z. View