Hostname: page-component-848d4c4894-8kt4b Total loading time: 0 Render date: 2024-06-19T18:11:11.677Z Has data issue: false hasContentIssue false

Mitochondrial calcium uniporter as a potential therapeutic strategy for Alzheimer’s disease

Published online by Cambridge University Press:  26 December 2019

Anila Venugopal
Human Molecular Genetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
Mahalaxmi Iyer
Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, Tamil Nadu, India
Venkatesh Balasubramanian
Human Molecular Genetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
Balachandar Vellingiri*
Human Molecular Genetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
Author for correspondence: Balachandar Vellingiri, Email:


Alzheimer’s disease (AD), a neurodegenerative disorder, is the leading cause of dementia in the world whose aetiology is still unclear. AD was always related to ageing though there have been instances where people at an early age also succumb to this disease. With medical advancements, the mortality rate has significantly reduced which also makes people more prone to AD. AD is rare, yet the prominent disease has been widely studied with several hypotheses trying to understand the workings of its onset. The most recent and popular hypothesis in AD is the involvement of mitochondrial dysfunction and calcium homeostasis in the development of the disease though their exact roles are not known. With the sudden advent of the mitochondrial calcium uniporter (MCU), many previously known pathological hallmarks of AD may be better understood. Several studies have shown the effect of excess calcium in mitochondria and the influence of MCU complex in mitochondrial function. In this article, we discuss the possible involvement of MCU in AD by linking the uniporter to mitochondrial dysfunction, calcium homeostasis, reactive oxygen species, neurotransmitters and the hallmarks of AD – amyloid plaque formation and tau tangle formation.

Review Article
© Scandinavian College of Neuropsychopharmacology 2019

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Alzheimer’s ACHW (2017) Calcium hypothesis of Alzheimer’s disease and brain aging: a framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 13(2), 178.CrossRefGoogle Scholar
Antony, AN, Paillard, M, Moffat, C, Juskeviciute, E, Correnti, J, Bolon, B, Rubin, E, Csordás, G, Seifert, EL, Hoek, JB and Hajnóczky, G (2016) MICU1 regulation of mitochondrial Ca2+ uptake dictates survival and tissue regeneration. Nature Communications 7, 10955.CrossRefGoogle Scholar
Baughman, JM, Perocchi, F, Girgis, HS, Plovanich, M, Belcher-Timme, CA, Sancak, Y, Bao, XR, Strittmatter, L, Goldberger, O, Bogorad, RL, Koteliansky, V and Mootha, VK (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476(7360), 341.CrossRefGoogle ScholarPubMed
Calingasan, NY, Uchida, K and Gibson, GE (1999) Protein‐bound acrolein. Journal of Neurochemistry 72(2), 751756.CrossRefGoogle ScholarPubMed
Connolly, J, Siderowf, A, Clark, CM, Mu, D and Pratico, D (2008) F2 isoprostane levels in plasma and urine do not support increased lipid peroxidation in cognitively impaired Parkinson disease patients. Cognitive and Behavioral Neurology 21(2), 8386.CrossRefGoogle Scholar
Coppotelli, G and Ross, JM (2016) Mitochondria in ageing and diseases: the super trouper of the cell. International Journal of Molecular Sciences 17(5), 711.CrossRefGoogle ScholarPubMed
Csordás, G, Golenár, T, Seifert, EL, Kamer, KJ, Sancak, Y, Perocchi, F, Moffat, C, Weaver, D, de la Fuente Perez, S, Bogorad, R, Koteliansky, V, Adijanto, J, Mootha, VK and Hajnóczky, G (2013) MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter. Cell Metabolism 17(6), 976987.CrossRefGoogle Scholar
Depp, C, Bas-Orth, C, Schroeder, L, Hellwig, A and Bading, H (2018) Synaptic activity protects neurons against calcium-mediated oxidation and contraction of mitochondria during excitotoxicity. Antioxidants and Redox Signaling 29(12), 11091124.CrossRefGoogle ScholarPubMed
De Stefani, D, Raffaello, A, Teardo, E, Szabò, I and Rizzuto, R (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476(7360), 336.CrossRefGoogle ScholarPubMed
DiMauro, S (2004) Mitochondrial diseases. Biochimica et Biophysica Acta (BBA) – Bioenergetics 1658(1–2), 8088.CrossRefGoogle ScholarPubMed
Etcheberrigaray, R, Hirashima, N, Nee, L, Prince, J, Govoni, S, Racchi, M, Tanzi, RE and Alkon, DL (1998) Calcium responses in fibroblasts from asymptomatic members of Alzheimer’s disease families. Neurobiology of Disease 5(1), 3745.CrossRefGoogle ScholarPubMed
Gherardi, G, Nogara, L, Ciciliot, S, Fadini, GP, Blaauw, B, Braghetta, P, Bonaldo, P, De Stefani, D, Rizzuto, R and Mammucari, C (2018) Loss of mitochondrial calcium uniporter rewires skeletal muscle metabolism and substrate preference. Cell Death and Differentiation 26(2), 1.Google ScholarPubMed
Gibson, GE and Thakkar, A (2017) Interactions of mitochondria/metabolism and calcium regulation in Alzheimer’s disease: a calcinist point of view. Neurochemical Research 42(6), 16361648.CrossRefGoogle ScholarPubMed
Giorgi, C, Agnoletto, C, Bononi, A, Bonora, M, De Marchi, E, Marchi, S, Missiroli, S, Patergnani, S, Poletti, F, Rimessi, A, Suski, JM, Wieckowski, MR and Pinton, P (2012) Mitochondrial calcium homeostasis as potential target for mitochondrial medicine. Mitochondrion 12(1), 7785.CrossRefGoogle ScholarPubMed
Görlach, A, Bertram, K, Hudecova, S and Krizanova, O (2015) Calcium and ROS: a mutual interplay. Redox Biology 6, 260271.CrossRefGoogle ScholarPubMed
Harrington, JL and Murphy, E (2015) The mitochondrial calcium uniporter: mice can live and die without it. Journal of Molecular and Cellular Cardiology 78, 4653.CrossRefGoogle Scholar
Hawking, ZL (2016) Alzheimer’s disease: the role of mitochondrial dysfunction and potential new therapies. Bioscience Horizons: The International Journal of Student Research, 9, hzw014.Google Scholar
Kannurpatti, SS (2017) Mitochondrial calcium homeostasis: implications for neurovascular and neurometabolic coupling. Journal of Cerebral Blood Flow and Metabolism 37(2), 381395.CrossRefGoogle ScholarPubMed
Kwon, S-K, Sando, III R, Lewis, TL, Hirabayashi, Y, Maximov, A and Polleux, F (2018) Correction: LKB1 regulates mitochondria-dependent presynaptic calcium clearance and neurotransmitter release properties at excitatory synapses along cortical axons. PLoS Biology 16(9), e3000040.CrossRefGoogle ScholarPubMed
Liao, Y, Dong, Y and Cheng, J (2017) The function of the mitochondrial calcium uniporter in neurodegenerative disorders. International Journal of Molecular Sciences 18(2), 248.CrossRefGoogle ScholarPubMed
Liao, Y, Hao, Y, Chen, H, He, Q, Yuan, Z and Cheng, J (2015) Mitochondrial calcium uniporter protein MCU is involved in oxidative stress-induced cell death. Protein & Cell 6(6), 434442.CrossRefGoogle ScholarPubMed
Lin, MT and Beal, MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113), 787.CrossRefGoogle ScholarPubMed
Litersky, JM, Johnson, GV, Jakes, R, Goedert, M, Michael, L and Seubert, P (1996) Tau protein is phosphorylated by cyclic AMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II within its microtubule-binding domains at Ser-262 and Ser-356. Biochemical Journal 316(2), 655660.CrossRefGoogle ScholarPubMed
Liu, JC, Liu, J, Holmström, KM, Menazza, S, Parks, RJ, Fergusson, MM, Yu, ZX, Springer, DA, Halsey, C, Liu, C, Murphy, E and Finkel, T (2016) MICU1 serves as a molecular gatekeeper to prevent in vivo mitochondrial calcium overload. Cell Reports 16(6):15611573.CrossRefGoogle ScholarPubMed
Logan, CV, Szabadkai, G, Sharpe, JA, Parry, DA, Torelli, S, Childs, A-M, Kriek, M, Phadke, R, Johnson, CA, Roberts, NY, Bonthron, DT, Pysden, KA, Whyte, T, Munteanu, I, Foley, AR, Wheway, G, Szymanska, K, Natarajan, S, Abdelhamed, ZA, Morgan, JE, Roper, H, Santen, GW, Niks, EH, van der Pol, WL, Lindhout, D, Raffaello, A, De Stefani, D, den Dunnen, JT, Sun, Y, Ginjaar, I, Sewry, CA, Hurles, M, Rizzuto, RUK10K Consortium, Duchen, MR, Muntoni, F and Sheridan, E (2014) Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nature Genetics 46(2), 188.CrossRefGoogle Scholar
Lovell, MA, Xiong, S, Xie, C, Davies, P and Markesbery, WR (2004) Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3. Journal of Alzheimer’s Disease 6(6), 659671.CrossRefGoogle ScholarPubMed
Mallilankaraman, K, Doonan, P, Cárdenas, C, Chandramoorthy, HC, Müller, M, Miller, R, Hoffman, NE, Gandhirajan, RK, Molgó, J, Birnbaum, MJ, Rothberg, BS, Mak, DO, Foskett, JK and Madesh, M (2012) MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival. Cell 151(3), 630644.CrossRefGoogle Scholar
Mammucari, C, Gherardi, G, Zamparo, I, Raffaello, A, Boncompagni, S, Chemello, F, Cagnin, S, Braga, A, Zanin, S, Pallafacchina, G, Zentilin, L, Sandri, M, De Stefani, D, Protasi, F, Lanfranchi, G and Rizzuto, R (2015) The mitochondrial calcium uniporter controls skeletal muscle trophism in vivo. Cell Reports 10(8), 12691279.CrossRefGoogle ScholarPubMed
M’Angale, P and Staveley, B (2017) Inhibition of mitochondrial calcium uptake 1 in Drosophila neurons. Genetics and Molecular Research 16(1), 104238.CrossRefGoogle ScholarPubMed
Moreira, PI, Carvalho, C, Zhu, X, Smith, MA and Perry, G (2010) Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1802(1), 210.CrossRefGoogle ScholarPubMed
Nakamura, S, Takamura, T, Matsuzawa-Nagata, N, Takayama, H, Misu, H, Noda, H, Nabemoto, S, Kurita, S, Ota, T, Ando, H, Miyamoto, K and Kaneko, S (2009) Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. The Journal of Biological Chemistry 284(22), 1480914818.CrossRefGoogle ScholarPubMed
Nichols, M, Elustondo, PA, Warford, J, Thirumaran, A, Pavlov, EV and Robertson, GS (2017) Global ablation of the mitochondrial calcium uniporter increases glycolysis in cortical neurons subjected to energetic stressors. Journal of Cerebral Blood Flow and Metabolism 37(8), 30273041.CrossRefGoogle ScholarPubMed
Pan, X, Liu, J, Nguyen, T, Liu, C, Sun, J, Teng, Y, Fergusson, MM, Rovira, II, Allen, M, Springer, DA, Aponte, AM, Gucek, M, Balaban, RS, Murphy, E and Finkel, T (2013) The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nature Cell Biology 15(12), 1464.CrossRefGoogle ScholarPubMed
Payne, BA and Chinnery, PF (2015) Mitochondrial dysfunction in aging: much progress but many unresolved questions. Biochimica et Biophysica Acta (BBA) – Bioenergetics 1847(11), 13471353.CrossRefGoogle ScholarPubMed
Piaceri, I, Rinnoci, V, Bagnoli, S, Failli, Y and Sorbi, S (2012) Mitochondria and Alzheimer’s disease. Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease 322(1), 3134.Google ScholarPubMed
Picone, P, Nuzzo, D, Caruana, L, Scafidi, V and Di Carlo, M (2014) Mitochondrial dysfunction: different routes to Alzheimer’s disease therapy. Oxidative Medicine and Cellular Longevity 2014(2), 780179.CrossRefGoogle ScholarPubMed
Pierrot, N, Ghisdal, P, Caumont, A and Octave, J (2004) Intraneuronal amyloid‐β1‐42 production triggered by sustained increase of cytosolic calcium concentration induces neuronal death. Journal of Neurochemistry 88(5), 11401150.CrossRefGoogle ScholarPubMed
Praticò, D, Lee, VM-Y, Trojanowski, JQ, Rokach, J and Fitzgerald, GA (1998) Increased F2-isoprostanes in Alzheimer’s disease: evidence for enhanced lipid peroxidation in vivo. The FASEB Journal 12(15), 17771783.CrossRefGoogle ScholarPubMed
Qiu, J, Tan, Y-W, Hagenston, AM, Martel, M-A, Kneisel, N, Skehel, PA, Wyllie, DJ, Bading, H and Hardingham, GE (2013) Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals. Nature Communications 4, 2034.CrossRefGoogle ScholarPubMed
Rasola, A and Bernardi, P (2007) The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis 12(5), 815833.CrossRefGoogle ScholarPubMed
Shuttleworth, CW, Brennan, AM and Connor, JA (2003) NAD (P) H fluorescence imaging of postsynaptic neuronal activation in murine hippocampal slices. The Journal of Neuroscience 23(8), 31963208.CrossRefGoogle ScholarPubMed
Soman, S, Keatinge, M, Moein, M, Da Costa, M, Mortiboys, H, Skupin, A, Sugunan, S, Bazala, M, Kuznicki, J and Bandmann, O (2017) Inhibition of the mitochondrial calcium uniporter rescues dopaminergic neurons in pink1−/− zebrafish. The European Journal of Neuroscience 45(4), 528535.CrossRefGoogle ScholarPubMed
Supnet, C and Bezprozvanny, I (2010) The dysregulation of intracellular calcium in Alzheimer disease. Cell Calcium 47(2), 183189.CrossRefGoogle ScholarPubMed
Tamagno, E, Parola, M, Bardini, P, Piccini, A, Borghi, R, Guglielmotto, M, Santoro, G, Davit, A, Danni, O, Smith, MA, Perry, G and Tabaton, M (2005) β‐Site APP cleaving enzyme up‐regulation induced by 4‐hydroxynonenal is mediated by stress‐activated protein kinases pathways. Journal of Neurochemistry 92(3), 628636.CrossRefGoogle ScholarPubMed
Trifunovic, A and Larsson, N (2008) Mitochondrial dysfunction as a cause of ageing. Journal of Internal Medicine 263(2), 167178.CrossRefGoogle ScholarPubMed
Verma, M, Callio, J, Otero, PA, Sekler, I, Wills, ZP and Chu, CT (2017) Mitochondrial calcium dysregulation contributes to dendrite degeneration mediated by PD/LBD-associated LRRK2 mutants. The Journal of Neuroscience 37(46), 1115111165.CrossRefGoogle ScholarPubMed
Waldeck-Weiermair, M, Malli, R, Parichatikanond, W, Gottschalk, B, Madreiter-Sokolowski, CT, Klec, C, Rost, R and Graier, WF (2015) Rearrangement of MICU1 multimers for activation of MCU is solely controlled by cytosolic Ca2+. Scientific Reports 5, 15602.CrossRefGoogle Scholar
Wang, X, Su, B, Lee, H, Li, X, Perry, G, Smith, MA and Zhu, X (2009) Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. The Journal of Neuroscience 29(28), 90909103.CrossRefGoogle ScholarPubMed
Yao, J, Irwin, RW, Zhao, L, Nilsen, J, Hamilton, RT and Brinton, RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences 106(34), 1467014675.CrossRefGoogle ScholarPubMed