ВЛИЯНИЕ ЛАКТАТА НА МИТОХОНДРИАЛЬНУЮ АКТИВНОСТЬ В КЛЕТКАХ ЭНДОТЕЛИЯ ПРИ ОСТРОМ ТОКСИЧЕСКОМ ДЕЙСТВИИ БЕТА-АМИЛОИДА IN VITRO
PDF

Ключевые слова

болезнь Альцгеймера
церебральный эндотелий
митохондриальная активность
флоретин

Как цитировать

Горина, Я. В., Хилажева, Е. Д., Мосягина, А. И., Харитонова, Е. В., Капкаева, М. Р., Стельмашук, Е. В., Исаев, Н. К., Розанова, Н. А., & Салмина, А. Б. (2022). ВЛИЯНИЕ ЛАКТАТА НА МИТОХОНДРИАЛЬНУЮ АКТИВНОСТЬ В КЛЕТКАХ ЭНДОТЕЛИЯ ПРИ ОСТРОМ ТОКСИЧЕСКОМ ДЕЙСТВИИ БЕТА-АМИЛОИДА IN VITRO. Российский физиологический журнал им. И. М. Сеченова, 108(6), 712–724. https://doi.org/10.31857/S0869813922060024

Аннотация

Установлено, что при остром токсическом действии бета-амилоида in vitro присутствие лактата во внеклеточном пространстве в дозозависимой манере снижает активность митохондрий в клетках эндотелия, блокада лактатных монокарбоксилатных транспортеров (МСТ) обладает таким же эффектом, но стимуляция лактатных GPR81-рецепторов на этих клетках вызывает увеличение активности митохондрий. Это позволяет предположить, что высокая концентрация лактата во внеклеточном пространстве подавляет активность митохондрий в клетках эндотелия, но это не связано с активностью GPR81-рецепторов. Вероятнее всего, эффекты GPR81 реализуются в присутствии более низких концентраций внеклеточного лактата. Поскольку развитие болезни Альцгеймера сопровождается снижением экспрессии изоформ MCT, определяющих транспорт и метаболизм лактата в нервных клетках, в комплексе с полученными нами данными дисрегуляция МСТ-транспортеров при болезни Альцгеймера способствует развитию митохондриальной дисфункции, а воспроизведение эффектов внеклеточного лактата путем активации GPR81-рецепторов частично компенсирует такое нарушение.

https://doi.org/10.31857/S0869813922060024
PDF

Литература

Scheltens P, Blennow K, Breteler MB, Strooper B, Frisoni GB, Salloway S, Flier WMV (2016) Alzheimer's disease. Lancet 388(10043):505–517. https://doi.org/10.1016/S0140-6736(15)01124-1

Charidimou A, Boulouis G, Gurol ME, Ayata C, Bacska BJ, Frosch MP, Viswanathan A, Greenberg SM (2017) Emerging concepts in sporadic cerebral amyloid angiopathy. Brain 140(7):1829–1850. https://doi.org/10.1093/brain/awx047

Kim SH, Ahn JH, Yang H, Lee P, Koh GY, Jeong Y (2020) Cerebral amyloid angiopathy aggravates perivascular clearance impairment in an Alzheimer's disease mouse model. Acta Neuropathol Commun 8(1):181. https://doi.org/10.1186/s40478-020-01042-0

Parodi-Rullán R, Ghiso J, Cabrera E, Rostagno A, Fossati S (2020) Alzheimer's amyloid β heterogeneous species differentially affect brain endothelial cell viability, blood-brain barrier integrity, and angiogenesis. Aging Cell 19(11):e13258. https://doi.org/10.1111/acel.13258

Iadecola C (2017) The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron 96(1):17–42. https://doi.org/10.1016/j.neuron.2017.07.030

Oldendorf WH, Cornford ME, Brown WJ (1977) The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol 1(5):409–417. https://doi.org/10.1002/ana.410010502

Zille M, Ikhsan M, Jiang Y, Lampe J, Wenzel J, Schwaninger M (2019) The impact of endothelial cell death in the brain and its role after stroke: A systematic review. Cell Stress 3(11):330–347. https://doi.org/10.15698/cst2019.11.203

Solesio ME, Peixoto PM, Debure L, Madamba SM, Leon MJ, Wisniewski T, Pavlov EV, Fossati S (2018) Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity. Aging Cell 17(4):e12787. https://doi.org/10.1111/acel.12787

Doll DN, Hu XH, Sun J, Lewis SE, Simpkins JW, Ren X (2015) Mitochondrial crisis in cerebrovascular endothelial cells opens the blood–brain barrier. Stroke 46(6):1681–1689. https://doi.org/10.1161/STROKEAHA.115.009099

Aliev G, Smith MA, Torre JC, Perry G (2004) Mitochondria as a primary target for vascular hypoperfusion and oxidative stress in Alzheimer's disease. Mitochondrion 4(5–6):649–463. https://doi.org/10.1016/j.mito.2004.07.018

Balietti M, Giorgetti B, Casoli T, Solazzi M, Tamagnini F, Burattini C, Aicardi G, Fattoretti P (2013) Early selective vulnerability of synapses and synaptic mitochondria in the hippocampal CA1 region of the Tg2576 mouse model of Alzheimer’s disease. J Alzheimers Dis 34:887–896. https://doi.org/10.3233/JAD-121711

Du H, Guo L, Yan S, Sosunov AA, McKhann GM, Yan SS (2010) Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model. Proc Natl Acad Sci USA 107:18670–18675. https://doi.org/10.1073/pnas.1006586107

Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 106:14670–14675. https://doi.org/ 10.1073/pnas.0903563106

Swerdlow RH, Khan SM (2004) A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease. Med Hypotheses 63(1):8–20. https://doi.org/10.1016/j.mehy.2003.12.045

Solé M, Miñano-Molina AJ, Unzeta M (2015) Cross-talk between Aβ and endothelial SSAO/VAP-1 accelerates vascular damage and Aβ aggregation related to CAA-AD. Neurobiol Aging 36(2):762–775. https://doi.org/10.1016/j.neurobiolaging.2014.09.030

Magistretti PJ, Allaman I (2018) Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci 19:235–249. https://doi.org/10.1038/nrn.2018.19

Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, Esparza LA, Reya T, Zhan L, Guo JY (2017) Glucose feeds the TCA cycle via circulating lactate. Nature 551:115–118. https://doi.org/10.1038/nature24057

Gerhart DZ, Enerson BE, Zhdankina OY, Leino RL, Drewes LR (1997) Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats. Am J Physiol 273(1 Pt 1):E207–E213. https://doi.org/10.1152/ajpendo.1997.273.1.E207

Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres B, Wu JQ (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34(36):11929–11947. https://doi.org/10.1523/JNEUROSCI.1860–14.2014

Хилажева ЕД, Писарева НВ, Моргун АВ, Бойцова ЕБ, Таранушенко ТЕ, Фролова ОВ, Салмина АБ (2017) Активация лактатных рецепторов GPR81 стимулирует митохондриальный биогенез в клетках эндотелия церебральных микрососудов. Анналы клиническ эксперим неврол 11(1): 34–39. [Khilazheva ED, Pisareva NV, Morgun AV, Boytsova EB, Taranushenko TE, Frolova OV, Salmina AB (2017) Activation of lactate receptors GPR81 stimulates mitochondrial biogenesis in endothelial cells of cerebral microvessels. Ann Clin Exper Neurol 11(1): 34–39. (In Russ)].

Parodi-Rullán R, Sone JY, Fossat S (2019) Endothelial Mitochondrial Dysfunction in Cerebral Amyloid Angiopathy and Alzheimer's Disease. J Alzheimers Dis 72(4):1019–1039. https://doi.org/10.3233/JAD-190357

Liu JP, Song M, Horton RM, Hu Y (2013) Reducing spread in climate model projections of a September ice-free Arctic. Proc Natl Acad Sci U S A 110:12571–12576. https://doi.org/10.1073/pnas.1219716110

Morgen K, Frölich L (2015) The metabolism hypothesis of Alzheimer's disease: from the concept of central insulin resistance and associated consequences to insulin therapy. J Neural Transm 122(4):499–504. https://doi.org/10.1007/s00702-015-1377-5

Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 106(34):14670–14675. https://doi.org/10.1073/pnas.0903563106

Dragicevic N, Mamcarz M, Zhu Y, Buzzeo R, Tan J, Arendash GW, Bradshaw PC (2010) Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regions and the degree of cognitive impairment in Alzheimer's transgenic mice. J Alzheimers Dis 20 Suppl 2:S535–S550. https://doi.org/10.3233/JAD-2010-100342

Hartl D, Schuldt V, Forler S, Zabel C, Klose J, Rohe MJ (2012) Presymptomatic alterations in energy metabolism and oxidative stress in the APP23 mouse model of Alzheimer disease. Proteom Res 11(6):3295–3304. https://doi.org/10.1021/pr300021e

Gan X, Huang S, Wu L, Wang Y, Hu G, Li G, Zhang H, Yu H, Swerdlow RH, Chen JX, Yan SS (2014) Inhibition of ERK-DLP1 signaling and mitochondrial division alleviates mitochondrial dysfunction in Alzheimer's disease cybrid cell. Biochim Biophys Acta 1842(2):220–231. https://doi.org/10.1016/j.bbadis.2013.11.009

Vlassenko AG, Vaishnavi SN, Couture L, Sacco D, Shannon BJ, Mach RH, Morris JC, Raichle ME, Mintun MA (2010) Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ ) deposition. Proc Natl Acad Sci USA 107(41):17763–17767. https://doi.org/10.1073/pnas.1010461107

Vlassenko AG, Gordon BA, Goyal MS, Su Y, Blazey TM, Durbin TJ, Couture LE, Christensen JJ, Jafri H, Morris JC, Raichle ME, Benzinger TL (2018) Aerobic glycolysis and tau deposition in preclinical Alzheimer's disease. Neurobiol Aging 67:95–98. https://doi.org/10.1016/j.neurobiolaging.2018.03.014

Newington JT, Rappon T, Albers S, Wong DY, Rylett RJ, Cumming RC (2012) Overexpression of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A in nerve cells confers resistance to amyloid β and other toxins by decreasing mitochondrial respiration and reactive oxygen species production. J Biol Chem 287(44):37245–37258. https://doi.org/10.1074/jbc.M112.366195

Garcia-Heredia JM, Carnero A (2015) Decoding Warburg's hypothesis: tumor-related mutations in the mitochondrial respiratory chain. Oncotarget 6(39):41582–41599. https://doi.org/10.18632/oncotarget.6057

Kim J, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3(3):177–185. https://doi.org/10.1016/j.cmet.2006.02.002

Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A (1996) Hypoxia response elements in the aldolase A, enolase, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271(51):32529–32537. https://doi.org/10.1074/jbc.271.51.32529

Zilberter M, Ivanov A, Ziyatdinova S, Mukhtarov M, Malkov A, Alpár A, Tortoriello G, Botting CH, Fülöp L, Osypov AA, Pitkänen A, Tanila H, Harkany T, Zilberter Y (2013) Dietary energy substrates reverse early neuronal hyperactivity in a mouse model of Alzheimer's disease. J Neurochem 125(1):157–171. https://doi.org/10.1111/jnc.12127

Morland C, Lauritzen KH, Puchades M, Holm-Hansen S, Andersson K, Gjedde A, Attramadal H, Storm-Mathisen J, Hildegard Bergersen L (2015) The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: Expression and action in brain. J Neurosci Res 93(7):1045–1055. https://doi.org/10.1002/jnr.23593

Lauritzen KH, Morland C, Puchades M, Holm-Hansen S, Hagelin EM, Lauritzen F, Attramadal H, Storm-Mathisen J, Gjedde A, Bergersen LH (2014) Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb Cortex 24(10):2784–2795. https://doi.org/10.1093/cercor/bht136

Vardjan N, Chowdhury HH, Horvat A, Velebit J, Malnar M, Muhič M, Kreft M, Krivec ŠG, Bobnar ST, Miš K, Pirkmajer S, Offermanns S, Henriksen G, Storm-Mathisen J, Bergersen LH, Zorec R (2018) Enhancement of Astroglial Aerobic Glycolysis by Extracellular Lactate-Mediated Increase in cAMP. Front Mol Neurosci 11:148. https://doi.org/10.3389/fnmol.2018.00148

Бойцова ЕБ, Моргун АВ, Мартынова ГП, Тохидпур A, Писарева НВ, Рузаева ВА, Салмина АБ (2016) GPR81 рецепторы лактата в регуляции функциональной активности клеток. Сибирск мед обозр 5:17–27. [Boytsova EB, Morgun AV, Martynova GP, Tohidpur A, Pisareva NV, Ruzaeva VA, Salmina AB (2016) GPR81 lactate receptors in the regulation of cell functional activity. Siberian Med Rev 5:17–27. (In Russ)].

Amer YO, Hebert-Chatelain E (2018) Mitochondrial cAMP-PKA signaling: What do we really know? Biochim Biophys Acta Bioenerg 1859(9):868–877. https://doi.org/10.1016/j.bbabio.2018.04.005

Dixit S, Fessel JP, Harrison FE (2017) Mitochondrial dysfunction in the APP/PSEN1 mouse model of Alzheimer's disease and a novel protective role for ascorbate. Free Radic Biol Med 112:515–523. https://doi.org/10.1016/j.freeradbiomed.2017.08.021

Iijima-Ando K, Hearn SA, Shenton C, Gatt A, Zhao L, Iijima K (2009) Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease. PLoS One 4(12):e8310. https://doi.org/10.1371/journal.pone.0008310

Canepa E, Domenicotti C, Marengo B, Passalacqua M, Marinari UM, Pronzato MA, Fedele E, Ricciarelli R (2013) Cyclic adenosine monophosphate as an endogenous modulator of the amyloid-β precursor protein metabolism. IUBMB Life 65(2):127–133. https://doi.org/10.1002/iub.1109

Terasaki T, Takakuwa S, Moritani S, Tsuji A (1991) Transport of monocarboxylic acids at the blood-brain barrier: studies with monolayers of primary cultured bovine brain capillary endothelial cells. J Pharmacol Exp Ther 258(3):932–937.

An Y, Varma VR, Varma S, Casanova R, Dammer E, Pletnikova O, Chia CW, Egan JM, Ferrucci L, Troncoso J, Levey AI, Lah J, Seyfried NT, Legido-Quigley C, O'Brien R, Thambisetty M (2018) Evidence for brain glucose dysregulation in Alzheimer's disease. Alzheimers Dement 14(3):318–329. https://doi.org/10.1016/j.jalz.2017.09.011

Lu W, Huang J, Sun S, Huang S, Gan S, Xu J, Yang M, Xu S, Jiang X (2015) Changes in lactate content and monocarboxylate transporter 2 expression in Aβ₂₅₋₃₅-treated rat model of Alzheimer's disease. Neurol Sci 36(6):871–876. https://doi.org/10.1007/s10072-015-2087-3

Hashimoto T, Hussien R, Cho HS, Kaufer D, Brooks GA (2008) Evidence for the mitochondrial lactate oxidation complex in rat neurons: demonstration of an essential component of brain lactate shuttles. PLoS One 3(8):e2915. https://doi.org/10.1371/journal.pone.0002915

Tescaroll F, Covolan L, Pellerin L (2014) Glutamate reduces glucose utilization while concomitantly enhancing AQP9 and MCT2 expression in cultured rat hippocampal neurons. Front Neurosci 8:246. https://doi.org/10.3389/fnins.2014.00246

Hashimoto T, Brooks GA (2008) Mitochondrial lactate oxidation complex and an adaptive role for lactate production. Med Sci Sports Exerc 40(3):486–494. https://doi.org/10.1249/MSS.0b013e31815fcb04

Nedergaar M, Goldman SA (1993) Carrier-mediated transport of lactic acid in cultured neurons and astrocytes. Am J Phys 265:R282–R289. https://doi.org/10.1152/ajpregu.1993.265.2.R282

Dienel GA (2012) Brain lactate metabolism: the discoveries and the controversies. J Cereb Blood Flow Metab 32:1107–1138. https://doi.org/10.1038/jcbfm.2011.175

Yu X, Zhang R, Wei C, Gao Y, Yu Y, Wang L, Jiang J, Zhang X, Li J, Chen X (2021) MCT2 overexpression promotes recovery of cognitive function by increasing mitochondrial biogenesis in a rat model of stroke. Anim Cells Syst (Seoul) 25(2):93–101. https://doi.org/10.1080/19768354.2021.1915379