Generic placeholder image

Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Review Article

Mitochondrial Calcium Signaling as a Therapeutic Target for Alzheimer’s Disease

Author(s): Aston J. Wu, Benjamin C.-K. Tong, Alexis S. Huang, Min Li and King-Ho Cheung*

Volume 17, Issue 4, 2020

Page: [329 - 343] Pages: 15

DOI: 10.2174/1567205016666191210091302

Price: $65


Mitochondria absorb calcium (Ca2+) at the expense of the electrochemical gradient generated during respiration. The influx of Ca2+ into the mitochondrial matrix helps maintain metabolic function and results in increased cytosolic Ca2+ during intracellular Ca2+ signaling. Mitochondrial Ca2+ homeostasis is tightly regulated by proteins located in the inner and outer mitochondrial membranes and by the cross-talk with endoplasmic reticulum Ca2+ signals. Increasing evidence indicates that mitochondrial Ca2+ overload is a pathological phenotype associated with Alzheimer’s Disease (AD). As intracellular Ca2+ dysregulation can be observed before the appearance of typical pathological hallmarks of AD, it is believed that mitochondrial Ca2+ overload may also play an important role in AD etiology. The high mitochondrial Ca2+ uptake can easily compromise neuronal functions and exacerbate AD progression by impairing mitochondrial respiration, increasing reactive oxygen species formation and inducing apoptosis. Additionally, mitochondrial Ca2+ overload can damage mitochondrial recycling via mitophagy. This review will discuss the molecular players involved in mitochondrial Ca2+ dysregulation and the pharmacotherapies that target this dysregulation. As most of the current AD therapeutics are based on amyloidopathy, tauopathy, and the cholinergic hypothesis, they achieve only symptomatic relief. Thus, determining how to reestablish mitochondrial Ca2+ homeostasis may aid in the development of novel AD therapeutic interventions.

Keywords: Calcium, Alzheimer's disease, mitochondria, hyperphosphorylation, neurodegenerative disorder, intracellular neurofibrillary tangles.

Gaugler J. 2019 Alzheimer’s disease facts and figures. Alzheimers Dement 2019; 15(3): 321-87.
Chakroborty S, Stutzmann GE. Calcium channelopathies and Alzheimer’s disease: Insight into therapeutic success and failures. Eur J Pharmacol 2014; 739: 83-95.
[] [PMID: 24316360]
Anekonda TS, Quinn JF. Calcium channel blocking as a therapeutic strategy for Alzheimer’s disease: The case for isradipine. Biochim Biophys Acta 2011; 1812(12): 1584-90.
[] [PMID: 21925266]
Kulshreshtha A, Piplani P. Current pharmacotherapy and putative disease-modifying therapy for Alzheimer’s disease. Neurol Sci 2016; 37(9): 1403-35.
[] [PMID: 27250365]
Toescu EC, Verkhratsky A. The importance of being subtle: Small changes in calcium homeostasis control cognitive decline in normal aging. Aging Cell 2007; 6(3): 267-73.
[] [PMID: 17517038]
LaFerla FM. Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci 2002; 3(11): 862-72.
[] [PMID: 12415294]
Raza M, Deshpande LS, Blair RE, Carter DS, Sombati S, DeLorenzo RJ. Aging is associated with elevated intracellular calcium levels and altered calcium homeostatic mechanisms in hippocampal neurons. Neurosci Lett 2007; 418(1): 77-81.
[] [PMID: 17374449]
Querfurth HW, Selkoe DJ. Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry 1994; 33(15): 4550-61.
[] [PMID: 8161510]
Bezprozvanny I, Mattson MP. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 2008; 31(9): 454-63.
[] [PMID: 18675468]
Buxbaum JD, Ruefli AA, Parker CA, Cypess AM, Greengard P. Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner. Proc Natl Acad Sci USA 1994; 91(10): 4489-93.
[] [PMID: 8183935]
Khachaturian ZS. Calcium hypothesis of Alzheimer’s disease and brain aging. Ann N Y Acad Sci 1994; 747(1): 1-11.
[] [PMID: 7847664]
Berridge MJ. Calcium hypothesis of Alzheimer’s disease. Pflugers Arch 2010; 459(3): 441-9.
[] [PMID: 19795132]
Sanz-Blasco S, Valero RA, Rodríguez-Crespo I, Villalobos C, Núñez L. Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PLoS One 2008; 3(7): e2718.
[] [PMID: 18648507]
Abeti R, Abramov AY. Mitochondrial Ca(2+) in neurodegenerative disorders. Pharmacol Res 2015; 99: 377-81.
[] [PMID: 26013908]
Wang X, Su B, Lee HG, et al. Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 2009; 29(28): 9090-103.
[] [PMID: 19605646]
Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta 2014; 1842(8): 1240-7.
[] [PMID: 24189435]
Baloyannis SJ, Costa V, Michmizos D. Mitochondrial alterations in Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2004; 19(2): 89-93.
[] [PMID: 15106389]
Rizzuto R, Pinton P, Brini M, Chiesa A, Filippin L, Pozzan T. Mitochondria as biosensors of calcium microdomains. Cell Calcium 1999; 26(5): 193-9.
[] [PMID: 10643557]
Gunter TE, Buntinas L, Sparagna G, Eliseev R, Gunter K. Mitochondrial calcium transport: mechanisms and functions. Cell Calcium 2000; 28(5-6): 285-96.
[] [PMID: 11115368]
Kumar U, Dunlop DM, Richardson JS. Mitochondria from Alzheimer’s fibroblasts show decreased uptake of calcium and increased sensitivity to free radicals. Life Sci 1994; 54(24): 1855-60.
[] [PMID: 8196502]
Sheehan JP, Swerdlow RH, Miller SW, et al. Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Alzheimer’s disease. J Neurosci 1997; 17(12): 4612-22.
[] [PMID: 9169522]
Rizzuto R, De Stefani D, Raffaello A, Mammucari C. Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 2012; 13(9): 566-78.
[] [PMID: 22850819]
Santo-Domingo J, Demaurex N. Calcium uptake mechanisms of mitochondria. Biochimica et Biophysica Acta (BBA)- Bioenergetics 2010; 1797(6-7): 907-12.
Payne R, Hoff H, Roskowski A, Foskett JK. MICU2 restricts spatial crosstalk between InsP3R and MCU channels by regulating threshold and gain of MICU1-mediated inhibition and activation of MCU. Cell Rep 2017; 21(11): 3141-54.
[] [PMID: 29241542]
Camara AKS, Zhou Y, Wen PC, Tajkhorshid E, Kwok WM. Mitochondrial VDAC1: A key gatekeeper as potential therapeutic target. Front Physiol 2017; 8: 460.
[] [PMID: 28713289]
Tan W, Colombini M. VDAC closure increases calcium ion flux. Biochimica et Biophysica Acta (BBA)- Biomembranes 2007; 1768(10): 2510-5.
Kornmann B. The molecular hug between the ER and the mitochondria. Curr Opin Cell Biol 2013; 25(4): 443-8.
[] [PMID: 23478213]
Szabadkai G, Bianchi K, Várnai P, et al. Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 2006; 175(6): 901-11.
[] [PMID: 17178908]
Patron M, Checchetto V, Raffaello A, et al. MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol Cell 2014; 53(5): 726-37.
[] [PMID: 24560927]
Mallilankaraman K, Doonan P, Cárdenas C, et al. MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell 2012; 151(3): 630-44.
[] [PMID: 23101630]
Dash RK, Beard DA. Analysis of cardiac mitochondrial Na+-Ca2+ exchanger kinetics with a biophysical model of mitochondrial Ca2+ handling suggests a 3:1 stoichiometry. J Physiol 2008; 586(13): 3267-85.
[] [PMID: 18467367]
Boyman L, Williams GS, Khananshvili D, Sekler I, Lederer WJ. NCLX: The mitochondrial sodium calcium exchanger. J Mol Cell Cardiol 2013; 59: 205-13.
[] [PMID: 23538132]
Rizzuto R, Bernardi P, Pozzan T. Mitochondria as all-round players of the calcium game. J Physiol 2000; 529(Pt 1): 37-47.
[] [PMID: 11080249]
Biasutto L, Azzolini M, Szabò I, Zoratti M. The mitochondrial permeability transition pore in AD 2016: An update. Biochim Biophys Acta 2016; 1863(10): 2515-30.
[] [PMID: 26902508]
Karch J, Molkentin JD. Identifying the components of the elusive mitochondrial permeability transition pore. Proc Natl Acad Sci USA 2014; 111(29): 10396-7.
[] [PMID: 25002521]
Du H, Guo L, Fang F, et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 2008; 14(10): 1097-105.
[] [PMID: 18806802]
Galluzzi L, Blomgren K, Kroemer G. Mitochondrial membrane permeabilization in neuronal injury. Nat Rev Neurosci 2009; 10(7): 481-94.
[] [PMID: 19543220]
Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J 1999; 341(Pt 2): 233-49.
[] [PMID: 10393078]
Shoshan-Barmatz V, Nahon-Crystal E, Shteinfer-Kuzmine A, Gupta R. VDAC1, mitochondrial dysfunction, and Alzheimer’s disease. Pharmacol Res 2018; 131: 87-101.
[] [PMID: 29551631]
Ben-Hail D, Shoshan-Barmatz V. VDAC1-interacting anion transport inhibitors inhibit VDAC1 oligomerization and apoptosis. Biochim Biophys Acta 2016; 1863(7 Pt A): 1612-23.
[] [PMID: 27064145]
Manczak M, Reddy PH. Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer’s disease. Hum Mol Genet 2012; 21(23): 5131-46.
[] [PMID: 22926141]
Caterino M, Ruoppolo M, Mandola A, Costanzo M, Orrù S, Imperlini E. Protein-protein interaction networks as a new perspective to evaluate distinct functional roles of voltage-dependent anion channel isoforms. Mol Biosyst 2017; 13(12): 2466-76.
[] [PMID: 29028058]
Smilansky A, Dangoor L, Nakdimon I, Ben-Hail D, Mizrachi D, Shoshan-Barmatz V. The voltage-dependent anion channel 1 mediates amyloid β toxicity and represents a potential target for Alzheimer disease therapy. J Biol Chem 2015; 290(52): 30670-83.
[] [PMID: 26542804]
Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. Mitochondria are a direct site of A β accumulation in Alzheimer’s disease neurons: Implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 2006; 15(9): 1437-49.
[] [PMID: 16551656]
Reddy PH. Is the mitochondrial outermembrane protein VDAC1 therapeutic target for Alzheimer’s disease? Biochim Biophys Acta 2013; 1832(1): 67-75.
[] [PMID: 22995655]
Keinan N, Tyomkin D, Shoshan-Barmatz V. Oligomerization of the mitochondrial protein voltage-dependent anion channel is coupled to the induction of apoptosis. Mol Cell Biol 2010; 30(24): 5698-709.
[] [PMID: 20937774]
Reddy PH, Beal MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: Implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med 2008; 14(2): 45-53.
[] [PMID: 18218341]
Calvo-Rodriguez M, Hernando-Perez E, Nuñez L, Villalobos C. Amyloid β oligomers increase ER-mitochondria Ca2+ cross talk in young hippocampal neurons and exacerbate aging-induced intracellular Ca2+ remodeling. Front Cell Neurosci 2019; 13: 22.
[] [PMID: 30800057]
Bertero E, Maack C. Calcium signaling and reactive oxygen species in mitochondria. Circ Res 2018; 122(10): 1460-78.
[] [PMID: 29748369]
Simon H-U, Haj-Yehia A, Levi-Schaffer F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 2000; 5(5): 415-8.
[] [PMID: 11256882]
Görlach A, Bertram K, Hudecova S, Krizanova O. Calcium and ROS: A mutual interplay. Redox Biol 2015; 6: 260-71.
[] [PMID: 26296072]
Liao Y, Hao Y, Chen H, He Q, Yuan Z, Cheng J. Mitochondrial calcium uniporter protein MCU is involved in oxidative stress-induced cell death. Protein Cell 2015; 6(6): 434-42.
[] [PMID: 25753332]
Dong Z, et al. Mitochondrial Ca2+ uniporter is a mitochondrial luminal redox sensor that augments MCU channel activity Molecular cell 2017; 65(6): 1014-28.
Demaurex N, Rosselin M. Redox control of mitochondrial calcium uptake. Mol Cell 2017; 65(6): 961-2.
[] [PMID: 28306510]
Jadiya P, Kolmetzky DW, Tomar D, et al. Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease. Nat Commun 2019; 10(1): 3885.
[] [PMID: 31467276]
Kostic M, Ludtmann MH, Bading H, et al. PKA phosphorylation of NCLX reverses mitochondrial calcium overload and depolarization, promoting survival of PINK1-deficient dopaminergic neurons. Cell Rep 2015; 13(2): 376-86.
[] [PMID: 26440884]
Ludtmann MHR, Kostic M, Horne A, Gandhi S, Sekler I, Abramov AY. LRRK2 deficiency induced mitochondrial Ca2+ efflux inhibition can be rescued by Na+/Ca2+/Li+ exchanger upregulation. Cell Death Dis 2019; 10(4): 265.
[] [PMID: 30890692]
Moriguchi S, Kita S, Fukaya M, et al. Reduced expression of Na+/Ca2+ exchangers is associated with cognitive deficits seen in Alzheimer’s disease model mice. Neuropharmacology 2018; 131: 291-303.
[] [PMID: 29274751]
Volgyi K, Juhász G, Kovacs Z, Penke B. Dysfunction of endoplasmic reticulum (ER) and mitochondria (MT) in Alzheimer’s disease: The role of the ER-MT cross-talk. Curr Alzheimer Res 2015; 12(7): 655-72.
[] [PMID: 26159206]
Area-Gomez E, de Groof A, Bonilla E, et al. A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease. Cell Death Dis 2018; 9(3): 335.
[] [PMID: 29491396]
Peng TI, Jou MJ. Oxidative stress caused by mitochondrial calcium overload. Ann N Y Acad Sci 2010; 1201(1): 183-8.
[] [PMID: 20649555]
Mattson MP. ER calcium and Alzheimer’s disease: In a state of flux. Sci Signal 2010; 3(114): pe10-0.
[] [PMID: 20332425]
Green KN, LaFerla FM. Linking calcium to Abeta and Alzheimer’s disease. Neuron 2008; 59(2): 190-4.
[] [PMID: 18667147]
Hansson Petersen CA, Alikhani N, Behbahani H, et al. The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci USA 2008; 105(35): 13145-50.
[] [PMID: 18757748]
Costa RO, Ferreiro E, Cardoso SM, Oliveira CR, Pereira CM. ER stress-mediated apoptotic pathway induced by Abeta peptide requires the presence of functional mitochondria. J Alzheimers Dis 2010; 20(2): 625-36.
[] [PMID: 20182029]
David DC, Hauptmann S, Scherping I, et al. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem 2005; 280(25): 23802-14.
[] [PMID: 15831501]
Kopeikina KJ, Carlson GA, Pitstick R, et al. Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer’s disease brain. Am J Pathol 2011; 179(4): 2071-82.
[] [PMID: 21854751]
Quintanilla RA, Matthews-Roberson TA, Dolan PJ, Johnson GV. Caspase-cleaved tau expression induces mitochondrial dysfunction in immortalized cortical neurons: Implications for the pathogenesis of Alzheimer disease. J Biol Chem 2009; 284(28): 18754-66.
[] [PMID: 19389700]
Cheung K-H, Shineman D, Müller M, et al. Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron 2008; 58(6): 871-83.
[] [PMID: 18579078]
Nelson O, Tu H, Lei T, Bentahir M, de Strooper B, Bezprozvanny I. Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest 2007; 117(5): 1230-9.
[] [PMID: 17431506]
Stutzmann GE, Smith I, Caccamo A, Oddo S, Parker I, Laferla F. Enhanced ryanodine-mediated calcium release in mutant PS1-expressing Alzheimer’s mouse models. Ann N Y Acad Sci 2007; 1097(1): 265-77.
[] [PMID: 17413028]
Tong BC-K, et al. Calcium signaling in Alzheimer's disease & therapies. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 2018.
Zampese E, Fasolato C, Kipanyula MJ, Bortolozzi M, Pozzan T, Pizzo P. Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk. Proc Natl Acad Sci USA 2011; 108(7): 2777-82.
[] [PMID: 21285369]
Sepulveda-Falla D, Barrera-Ocampo A, Hagel C, et al. Familial Alzheimer’s disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis. J Clin Invest 2014; 124(4): 1552-67.
[] [PMID: 24569455]
Supnet C, Bezprozvanny I. Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer’s disease. J Alzheimers Dis 2010; 20(2): S487-98.
[] [PMID: 20413848]
El Idrissi A. Taurine increases mitochondrial buffering of calcium: Role in neuroprotection. Amino Acids 2008; 34(2): 321-8.
[] [PMID: 16955229]
Szabadkai G, Duchen MR. Mitochondria: The hub of cellular Ca2+ signaling. Physiology (Bethesda) 2008; 23(2): 84-94.
[] [PMID: 18400691]
De La Fuente S, Lambert JP, Nichtova Z, et al. Spatial separation of mitochondrial calcium uptake and extrusion for energy-efficient mitochondrial calcium signaling in the heart. Cell reports 2018; 24(12): 3099-107..
Perry GM, Tallaksen-Greene S, Kumar A, et al. Mitochondrial calcium uptake capacity as a therapeutic target in the R6/2 mouse model of Huntington’s disease. Hum Mol Genet 2010; 19(17): 3354-71.
[] [PMID: 20558522]
Santulli G, Xie W, Reiken SR, Marks AR. Mitochondrial calcium overload is a key determinant in heart failure. Proc Natl Acad Sci USA 2015; 112(36): 11389-94.
[] [PMID: 26217001]
Brini M, Pinton P, King MP, Davidson M, Schon EA, Rizzuto R. A calcium signaling defect in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation deficiency. Nat Med 1999; 5(8): 951-4.
[] [PMID: 10426322]
Shoffner JM, Watts RL, Juncos JL, Torroni A, Wallace DC. Mitochondrial oxidative phosphorylation defects in Parkinson’s disease. Ann Neurol 1991; 30(3): 332-9.
[] [PMID: 1952821]
Newsholme P, Haber EP, Hirabara SM, et al. Diabetes associated cell stress and dysfunction: Role of mitochondrial and non-mitochondrial ROS production and activity. J Physiol 2007; 583(Pt 1): 9-24.
[] [PMID: 17584843]
Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443(7113): 787-95.
[] [PMID: 17051205]
Ruiz-Meana M, Abellán A, Miró-Casas E, Garcia-Dorado D. Opening of mitochondrial permeability transition pore induces hypercontracture in Ca2+ overloaded cardiac myocytes. Basic Res Cardiol 2007; 102(6): 542-52.
[] [PMID: 17891523]
Nicholls DG. Mitochondrial calcium function and dysfunction in the central nervous system. Biochim Biophys Acta 2009; 1787(11): 1416-24.
[] [PMID: 19298790]
Lustbader JW, Cirilli M, Lin C, et al. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 2004; 304(5669): 448-52.
[] [PMID: 15087549]
Filadi R, Greotti E, Turacchio G, Luini A, Pozzan T, Pizzo P. Presenilin 2 modulates endoplasmic reticulum-mitochondria coupling by tuning the antagonistic effect of mitofusin 2. Cell Rep 2016; 15(10): 2226-38.
[] [PMID: 27239030]
Christen Y. Oxidative stress and Alzheimer disease. Am J Clin Nutr 2000; 71(2): 621S-9S.
[] [PMID: 10681270]
Ansari MA, Abdul HM, Joshi G, Opii WO, Butterfield DA. Protective effect of quercetin in primary neurons against Abeta(1-42): relevance to Alzheimer’s disease. J Nutr Biochem 2009; 20(4): 269-75.
[] [PMID: 18602817]
Yao J, Du H, Yan S, et al. Inhibition of amyloid-β (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer’s disease. J Neurosci 2011; 31(6): 2313-20.
[] [PMID: 21307267]
Rhein V, Song X, Wiesner A, et al. Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci USA 2009; 106(47): 20057-62.
[] [PMID: 19897719]
Tarasov AI, Griffiths EJ, Rutter GA. Regulation of ATP production by mitochondrial Ca(2+). Cell Calcium 2012; 52(1): 28-35.
[] [PMID: 22502861]
Haumann J, Dash RK, Stowe DF, Boelens AD, Beard DA, Camara AK. Mitochondrial free [Ca2+] increases during ATP/ADP antiport and ADP phosphorylation: Exploration of mechanisms. Biophys J 2010; 99(4): 997-1006.
[] [PMID: 20712982]
Jouaville LS, Pinton P, Bastianutto C, Rutter GA, Rizzuto R. Regulation of mitochondrial ATP synthesis by calcium: Evidence for a long-term metabolic priming. Proc Natl Acad Sci USA 1999; 96(24): 13807-12.
[] [PMID: 10570154]
Toglia P, Cheung KH, Mak DO, Ullah G. Impaired mitochondrial function due to familial Alzheimer’s disease-causing presenilins mutants via Ca(2+) disruptions. Cell Calcium 2016; 59(5): 240-50.
[] [PMID: 26971122]
Sarasija S, Laboy JT, Ashkavand Z, Bonner J, Tang Y, Norman KR. Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans eLife 2018;. 7e33052
[] [PMID: 29989545]
Oksanen M, Petersen AJ, Naumenko N, et al. PSEN1 mutant iPSC-derived model reveals severe astrocyte pathology in Alzheimer’s disease. Stem Cell Reports 2017; 9(6): 1885-97.
[] [PMID: 29153989]
Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 2004; 287(4): C817-33.
[] [PMID: 15355853]
Kerr JS, Adriaanse BA, Greig NH, et al. Mitophagy and Alzheimer’s disease: cellular and molecular mechanisms. Trends Neurosci 2017; 40(3): 151-66.
[] [PMID: 28190529]
Sorrentino V, Romani M, Mouchiroud L, et al. Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature 2017; 552(7684): 187-93.
[] [PMID: 29211722]
Lee J-H, Yu WH, Kumar A, et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 2010; 141(7): 1146-58.
[] [PMID: 20541250]
Fang EF, Hou Y, Palikaras K, et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci 2019; 22(3): 401-12.
[] [PMID: 30742114]
Martín-Maestro P, Gargini R, A Sproul A, et al. Mitophagy failure in fibroblasts and iPSC-derived neurons of Alzheimer’s disease-associated presenilin 1 mutation. Front Mol Neurosci 2017; 10: 291.
[] [PMID: 28959184]
Lee J-H, McBrayer MK, Wolfe DM, et al. Presenilin 1 maintains lysosomal Ca2+ homeostasis via TRPML1 by regulating vATPase-mediated lysosome acidification. Cell Rep 2015; 12(9): 1430-44.
[] [PMID: 26299959]
Mairet-Coello G, Courchet J, Pieraut S, Courchet V, Maximov A, Polleux F. The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through Tau phosphorylation. Neuron 2013; 78(1): 94-108.
[] [PMID: 23583109]
Akundi RS, Huang Z, Eason J, et al. Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS One 2011; 6(1)e16038
[] [PMID: 21249202]
Gandhi S, Wood-Kaczmar A, Yao Z, et al. PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 2009; 33(5): 627-38.
[] [PMID: 19285945]
Heeman B, Van den Haute C, Aelvoet SA, et al. Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance. J Cell Sci 2011; 124(Pt 7): 1115-25.
[] [PMID: 21385841]
Pérez MJ, Jara C, Quintanilla RA. Contribution of tau pathology to mitochondrial impairment in neurodegeneration. Front Neurosci 2018; 12: 441.
[] [PMID: 30026680]
Cassano T, Pace L, Bedse G, et al. Glutamate and mitochondria: two prominent players in the oxidative stress-induced neurodegeneration. Curr Alzheimer Res 2016; 13(2): 185-97.
[] [PMID: 26679860]
von Bernhardi R, Eugenín-von Bernhardi L, Eugenín J. Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci 2015; 7: 124.
[] [PMID: 26257642]
Sanz-Blasco S, Calvo-Rodriguez M, Caballero E, Garcia-Durillo M, Nunez L, Villalobos C. Is it all said for NSAIDs in Alzheimer’s disease? Role of mitochondrial calcium uptake. Curr Alzheimer Res 2018; 15(6): 504-10.
[] [PMID: 29283047]
Valaasani KR, Sun Q, Hu G, et al. Identification of human ABAD inhibitors for rescuing Aβ-mediated mitochondrial dysfunction. Curr Alzheimer Res 2014; 11(2): 128-36.
[] [PMID: 24479630]
Tsai P-H, Cummings JL. Treatment of Alzheimer’s disease. Behav Neurol Demen 2016,415.
Zheng H, Fridkin M, Youdim M. New approaches to treating Alzheimer’s disease. Perspect Med Chem 2015; 7: 1-8.
Association AS. 2018 Alzheimer’s disease facts and figures. Alzheimers Dement 2018; 14(3): 367-429.
Gilman S, Koller M, Black RS, et al. AN1792(QS-21)-201 Study Team. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005; 64(9): 1553-62.
[] [PMID: 15883316]
Fox NC, Black RS, Gilman S, et al. AN1792(QS-21)-201 Study. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 2005; 64(9): 1563-72.
[] [PMID: 15883317]
LEHNINGER. AL, The coupling of Ca1+ transport to electron transport in mitochondria The molecular basis of electron transport. Academic Press NY 1972; pp. 133-51.
Kirichok Y, Krapivinsky G, Clapham DE. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 2004; 427(6972): 360-4.
[] [PMID: 14737170]
Chaudhuri D, Sancak Y, Mootha VK, Clapham DE. MCU encodes the pore conducting mitochondrial calcium currents. eLife 2013;. 2e00704
[] [PMID: 23755363]
Cao C, Wang S, Cui T, Su XC, Chou JJ. Ion and inhibitor binding of the double-ring ion selectivity filter of the mitochondrial calcium uniporter. Proc Natl Acad Sci USA 2017; 114(14): E2846-51.
[] [PMID: 28325874]
Viola HM, Arthur PG, Hool LC. Evidence for regulation of mitochondrial function by the L-type Ca2+ channel in ventricular myocytes. J Mol Cell Cardiol 2009; 46(6): 1016-26.
[] [PMID: 19166857]
Raiteri L, Stigliani S, Zedda L, Raiteri M, Bonanno G. Multiple mechanisms of transmitter release evoked by “pathologically” elevated extracellular [K+]: Involvement of transporter reversal and mitochondrial calcium. J Neurochem 2002; 80(4): 706-14.
[] [PMID: 11841577]
Xu L, Tripathy A, Pasek DA, Meissner G. Potential for pharmacology of ryanodine receptor/calcium release channels. Ann N Y Acad Sci 1998; 853(1): 130-48.
[PMID: 10603942]
Amann R, Maggi CA. Ruthenium red as a capsaicin antagonist. Life Sci 1991; 49(12): 849-56.
[] [PMID: 1715010]
Hymel L, Schindler H, Inui M, Fleischer S. Reconstitution of purified cardiac muscle calcium release channel (ryanodine receptor) in planar bilayers. Biochem Biophys Res Commun 1988; 152(1): 308-14.
[] [PMID: 2451914]
Czirják G, Enyedi P. Formation of functional heterodimers between the TASK-1 and TASK-3 two-pore domain potassium channel subunits. J Biol Chem 2002; 277(7): 5426-32.
[] [PMID: 11733509]
de Jesús García-Rivas G, Guerrero-Hernández A, Guerrero-Serna G, Rodríguez-Zavala JS, Zazueta C. Inhibition of the mitochondrial calcium uniporter by the oxo-bridged dinuclear ruthenium amine complex (Ru360) prevents from irreversible injury in postischemic rat heart. FEBS J 2005; 272(13): 3477-88.
[] [PMID: 15978050]
Yeung HM, Kravtsov GM, Ng KM, Wong TM, Fung ML. Chronic intermittent hypoxia alters Ca2+ handling in rat cardiomyocytes by augmented Na+/Ca2+ exchange and ryanodine receptor activities in ischemia-reperfusion. Am J Physiol Cell Physiol 2007; 292(6): C2046-56.
[] [PMID: 17267548]
Lee K-S, Huh S, Lee S, et al. Altered ER-mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models. Proc Natl Acad Sci USA 2018; 115(38): E8844-53.
[] [PMID: 30185553]
Yu S, Zheng S, Leng J, Wang S, Zhao T, Liu J. Inhibition of mitochondrial calcium uniporter protects neurocytes from ischemia/reperfusion injury via the inhibition of excessive mitophagy. Neurosci Lett 2016; 628: 24-9.
[] [PMID: 27288019]
Chang KT, Niescier RF, Min K-T. Mitochondrial matrix Ca2+ as an intrinsic signal regulating mitochondrial motility in axons. Proc Natl Acad Sci USA 2011; 108(37): 15456-61.
[] [PMID: 21876166]
Woods JJ, Nemani N, Shanmughapriya S, et al. A Selective and cell-permeable mitochondrial calcium uniporter (MCU) inhibitor preserves mitochondrial bioenergetics after hypoxia/reoxygenation injury. ACS Cent Sci 2019; 5(1): 153-66.
[] [PMID: 30693334]
Csordás G, Várnai P, Golenár T, Sheu SS, Hajnóczky G. Calcium transport across the inner mitochondrial membrane: Molecular mechanisms and pharmacology. Mol Cell Endocrinol 2012; 353(1-2): 109-13.
[] [PMID: 22123069]
Yoshida S, Fujimura K, Matsuda Y. Effects of quinidine and quinine on the excitability of pyramidal neurons in guinea-pig hippocampal slices. Pflugers Arch 1986; 406(5): 544-6.
[] [PMID: 3714453]
Baker SP, Sumners C, Pitha J, Raizada MK. Characteristics of the β-adrenoreceptor from neuronal and glial cells in primary cultures of rat brain. J Neurochem 1986; 47(4): 1318-26.
[] [PMID: 2875131]
Komai H, McDowell TS. Differential effects of bupivacaine and tetracaine on capsaicin-induced currents in dorsal root ganglion neurons. Neurosci Lett 2005; 380(1-2): 21-5.
[] [PMID: 15854744]
Kon N, Murakoshi M, Isobe A, Kagechika K, Miyoshi N, Nagayama T. DS16570511 is a small-molecule inhibitor of the mitochondrial calcium uniporter. Cell Death Discov 2017; 3: 17045.
[] [PMID: 28725491]
Kon N, Satoh A, Miyoshi N. A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition. Sci Rep 2017; 7(1): 3864.
[] [PMID: 28634393]
Payne R, et al. The MCU Inhibitor Ds16570511 has off-target effects on mitochondrial membrane potential. Biophys J 2019; 116(3): 270a.
Schwartz J, Holmuhamedov E, Zhang X, Lovelace GL, Smith CD, Lemasters JJ. Minocycline and doxycycline, but not other tetracycline-derived compounds, protect liver cells from chemical hypoxia and ischemia/reperfusion injury by inhibition of the mitochondrial calcium uniporter. Toxicol Appl Pharmacol 2013; 273(1): 172-9.
[] [PMID: 24012766]
Choi Y, Kim HS, Shin KY, et al. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models. Neuropsychopharmacology 2007; 32(11): 2393-404.
[] [PMID: 17406652]
Cheng S, Hou J, Zhang C, et al. Minocycline reduces neuroinflammation but does not ameliorate neuron loss in a mouse model of neurodegeneration. Sci Rep 2015; 5: 10535.
[] [PMID: 26000566]
Arduino DM, Wettmarshausen J, Vais H, Navas-Navarro P, et al. Systematic identification of MCU modulators by orthogonal interspecies chemical screening. Molecular cell 2017; 67(4): 711-23.
Kapuscinski J, Darzynkiewicz Z. Interactions of antitumor agents Ametantrone and Mitoxantrone (Novatrone) with double-stranded DNA. Biochem Pharmacol 1985; 34(24): 4203-13.
[] [PMID: 4074383]
Boland MP, Fitzgerald KA, O’Neill LA. Topoisomerase II is required for mitoxantrone to signal nuclear factor κ B activation in HL60 cells. J Biol Chem 2000; 275(33): 25231-8.
[] [PMID: 10940316]
Smith PJ, Morgan SA, Fox ME, Watson JV. Mitoxantrone-DNA binding and the induction of topoisomerase II associated DNA damage in multi-drug resistant small cell lung cancer cells. Biochem Pharmacol 1990; 40(9): 2069-78.
[] [PMID: 2173600]
Gincel D, Zaid H, Shoshan-Barmatz V. Calcium binding and translocation by the voltage-dependent anion channel: A possible regulatory mechanism in mitochondrial function. Biochem J 2001; 358(Pt 1): 147-55.
[] [PMID: 11485562]
Dubey AK, Godbole A, Mathew MK. Regulation of VDAC trafficking modulates cell death. Cell Death Discov 2016; 2: 16085.
[] [PMID: 28028442]
Magrì A, Reina S, De Pinto V. VDAC1 as pharmacological target in cancer and neurodegeneration: focus on its role in apoptosis. Front Chem 2018; 6: 108.
[] [PMID: 29682501]
Yoo BC, Fountoulakis M, Cairns N, Lubec G. Changes of voltage-dependent anion-selective channel proteins VDAC1 and VDAC2 brain levels in patients with Alzheimer’s disease and Down syndrome. Electrophoresis 2001; 22(1): 172-9.
[<172:AID-ELPS172>3.0.CO;2-P] [PMID: 11197169]
Cuadrado-Tejedor M, Vilariño M, Cabodevilla F, Del Río J, Frechilla D, Pérez-Mediavilla A. Enhanced expression of the voltage-dependent anion channel 1 (VDAC1) in Alzheimer’s disease transgenic mice: an insight into the pathogenic effects of amyloid-β. J Alzheimers Dis 2011; 23(2): 195-206.
[] [PMID: 20930307]
Ben-Hail D, Begas-Shvartz R, Shalev M, et al. Novel compounds targeting the mitochondrial protein VDAC1 inhibit apoptosis and protect against mitochondrial dysfunction. J Biol Chem 2016; 291(48): 24986-5003.
[] [PMID: 27738100]
Skonieczna M, Cieslar-Pobuda A, Saenko Y, et al. The impact of DIDS-induced inhibition of voltage-dependent anion channels (VDAC) on cellular response of lymphoblastoid cells to ionizing radiation. Med Chem 2017; 13(5): 477-83.
[] [PMID: 28427245]
Thinnes FP, Flörke H, Winkelbach H, et al. Channel active mammalian porin, purified from crude membrane fractions of human B lymphocytes or bovine skeletal muscle, reversibly binds the stilbene-disulfonate group of the chloride channel blocker DIDS. Biol Chem Hoppe Seyler 1994; 375(5): 315-22.
[] [PMID: 8074805]
Benítez-Rangel E, López-Méndez MC, García L, Guerrero-Hernández A. DIDS (4,4′-Diisothiocyanatostilbene-2,2′-disulfonate) directly inhibits caspase activity in HeLa cell lysates. Cell Death Discov 2015; 1: 15037.
[] [PMID: 27551467]
Parnis J, Montana V, Delgado-Martinez I, et al. Mitochondrial exchanger NCLX plays a major role in the intracellular Ca2+ signaling, gliotransmission, and proliferation of astrocytes. J Neurosci 2013; 33(17): 7206-19.
[] [PMID: 23616530]
Tanveer A, Virji S, Andreeva L, et al. Involvement of cyclophilin D in the activation of a mitochondrial pore by Ca2+ and oxidant stress. Eur J Biochem 1996; 238(1): 166-72.
[] [PMID: 8665934]
Sharov VG, Todor A, Khanal S, Imai M, Sabbah HN. Cyclosporine A attenuates mitochondrial permeability transition and improves mitochondrial respiratory function in cardiomyocytes isolated from dogs with heart failure. J Mol Cell Cardiol 2007; 42(1): 150-8.
[] [PMID: 17070837]
Chen J, Yang F, Yu X, Yu Y, Gong Y. Cyclosporine A promotes cell proliferation, collagen and α-smooth muscle actin expressions in rat gingival fibroblasts by Smad3 activation and miR-29b suppression. J Periodontal Res 2016; 51(6): 735-47.
[] [PMID: 26738448]
Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol 1999; 246(5): 339-46.
[] [PMID: 10399863]
Teplova V, Evtodienko Y, Odinokova I, Kruglov A, Kudrjavtsev A. Suppression of mitochondrial permeability transition pore and induction of lymphoma P388 cell death by cyclosporin A. IUBMB Life 2000; 50(1): 75-80.
[] [PMID: 11087125]
Khaspekov L, Friberg H, Halestrap A, Viktorov I, Wieloch T. Cyclosporin A and its nonimmunosuppressive analogue N-Me-Val-4-cyclosporin A mitigate glucose/oxygen deprivation-induced damage to rat cultured hippocampal neurons. Eur J Neurosci 1999; 11(9): 3194-8.
[] [PMID: 10510183]
Clarke SJ, McStay GP, Halestrap AP. Sanglifehrin A acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-D at a different site from cyclosporin A. J Biol Chem 2002; 277(38): 34793-9.
[] [PMID: 12095984]
Azzolin L, Antolini N, Calderan A, et al. Antamanide, a derivative of Amanita phalloides, is a novel inhibitor of the mitochondrial permeability transition pore. PLoS One 2011; 6(1)e16280
[] [PMID: 21297983]
Teixeira J, Oliveira C, Cagide F, et al. Discovery of a new mitochondria permeability transition pore (mPTP) inhibitor based on gallic acid. J Enzyme Inhib Med Chem 2018; 33(1): 567-76.
[] [PMID: 29513043]
Bachurin S, Bukatina E, Lermontova N, et al. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann N Y Acad Sci 2001; 939(1): 425-35.
[] [PMID: 11462798]
Grigorev VV, Dranyi OA, Bachurin SO. Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med 2003; 136(5): 474-7.
[] [PMID: 14968164]
Lermontova NN, Redkozubov AE, Shevtsova EF, Serkova TP, Kireeva EG, Bachurin SO. Dimebon and tacrine inhibit neurotoxic action of β-amyloid in culture and block L-type Ca(2+) channels. Bull Exp Biol Med 2001; 132(5): 1079-83.
[] [PMID: 11865327]
Bachurin SO, Shevtsova EP, Kireeva EG, Oxenkrug GF, Sablin SO. Mitochondria as a target for neurotoxins and neuroprotective agents. Ann N Y Acad Sci 2003; 993(1): 334-44.
[] [PMID: 12853325]
Shevtsova EF, Vinogradova DV, Kireeva EG, Reddy VP, Aliev G, Bachurin SO. Dimebon attenuates the Aβ-induced mitochondrial permeabilization. Curr Alzheimer Res 2014; 11(5): 422-9.
[] [PMID: 24801220]
Mullard A. Symptomatic AD treatment fails in first phase III. Nature Publishing Group 2016.
Eckert SH, Gaca J, Kolesova N, Friedland K, Eckert GP, Muller WE. Mitochondrial pharmacology of dimebon (latrepirdine) calls for a new look at its possible therapeutic potential in Alzheimer’s disease. Aging Dis 2018; 9(4): 729-44.
[] [PMID: 30090660]
Perez SE, Nadeem M, Sadleir KR, et al. Dimebon alters hippocampal amyloid pathology in 3xTg-AD mice. Int J Physiol Pathophysiol Pharmacol 2012; 4(3): 115-27.
[PMID: 23071869]
Wang J, Ferruzzi MG, Varghese M, et al. Preclinical study of dimebon on β-amyloid-mediated neuropathology in Alzheimer’s disease. Mol Neurodegener 2011; 6(1): 7.
[] [PMID: 21247479]
Calvo-Rodríguez M, Núñez L, Villalobos C. Non-steroidal anti-inflammatory drugs (NSAIDs) and neuroprotection in the elderly: A view from the mitochondria. Neural Regen Res 2015; 10(9): 1371-2.
[] [PMID: 26604882]
Wang X, Zhao XL, Xu LL, et al. Mitophagy in APPsw/PS1dE9 transgenic mice and APPsw stably expressing in HEK293 cells. Eur Rev Med Pharmacol Sci 2015; 19(23): 4595-602.
[PMID: 26698257]
Goiran T, Duplan E, Chami M, et al. β-Amyloid precursor protein intracellular domain controls mitochondrial function by modulating phosphatase and tensin homolog-induced kinase 1 transcription in cells and in alzheimer mice models. Biol Psychiatry 2018; 83(5): 416-27.
[] [PMID: 28587718]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy