Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels
Open accessAbstract
Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%-2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death.
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Mutations in p97 in mice and humans cause mitochondrial swelling, cristae disruption, oxidative stress, and decreased ATP, resulting in skeletal muscle atrophy and weakness.
“Mutations in p97 in mice [173] and humans [174] cause mitochondrial swelling, cristae disruption, oxidative stress, and decreased ATP, resulting in skeletal muscle atrophy and weakness.”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [174]
Mutations in VCP could cause mitochondrial uncoupling and play a role in frontotemporal dementia (IBMPFD) and some familial cases of amyotrophic lateral sclerosis.
“Mutations in VCP (Valosin-Containing Protein), a type II AAA+ ATPase family, could also cause mitochondrial uncoupling and play a role in frontotemporal dementia (IBMPFD) and some familial cases of amyotrophic lateral sclerosis, as it could sensitize deficient neuronal cells to subsequent stress, such as ischemia and other conditions requiring high energy demand [290].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [290]
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“and Reduced ATP Levels”
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“Interestingly, the levels of UCPs, key regulators of mitochondrial function, have previously been shown to be altered in skeletal muscle biopsies from rat and mouse ALS models and human ALS patients (Dupuis et al., 2003; Patel et al., 2010; Smittkamp et al., 2010).”
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“Mutations in VCP (Valosin-Containing Protein), a type II AAA+ ATPase family, could also cause mitochondrial uncoupling and play a role in frontotemporal dementia (IBMPFD) and some familial cases of amyotrophic lateral sclerosis, as it could sensitize deficient neuronal cells to subsequent stress, such as ischemia and…”
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“…inhibit the UPS (Tresse et al., 2010), whereas some of the VCP-mediated events mentioned above were altered (Ju et al., 2009; Tresse et al., 2010; Bartolome et al., 2013; Fujita et al., 2013; Kim et al., 2013), suggesting that the pathology caused by mutant VCP likely involves essential…”
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“Damage to mitochondrial ATP production is a prominent feature of ALS [9,33,34,44].”
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“These findings are consistent with uncoupling of oxidative phosphorylation in VCP-mutant MNs as previously reported in other model systems (Bartolome et al., 2013).”
ResultSelf-citationGene-specific mitochondria dysfunctions in human TARDBP and C9ORF72 fibroblasts
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“Moreover, changes in bioenergetics properties were recently shown in fibroblasts from sporadic ALS patients [4, 18] as well as in fibroblasts from ALS patients carrying mutations in SOD1 and VCP1 genes [5, 8].”
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“For example, mutations in critical components of MAD, such as Cdc48p and VCP result in decreased membrane potential and cell death, both of which are hallmarks of aging and disease (Bartolome et al., 2013; Braun et al., 2006).”
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“Furthermore, VCP/p97 mutations, which are found in $2% of familial ALS patients (Johnson et al., 2010), can cause mitochondrial uncoupling and an ensuing decreased ATP production in patients' fibroblasts (Bartolome et al., 2013).”
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“…and in fibroblasts with VCP mutations, Bartolome et al. demonstrated that VCP deficiency causes significant mitochondrial uncoupling, leading to decreased mitochondrial membrane potential, increased mitochondrial oxygen consumption and reduction of cellular ATP production (Bartolome et al., 2013).”
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Measurement of Mitochondrial NADH and FAD Autofluorescence in Live Cells
Bartolomé, F. B., & Abramov, A. Y. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-2257-4_23 · Cited by 131 · see citing works
“Fluorescent imaging of mitochondria in living cells provides a helpful tool to monitor mitochondrial function in more “native” conditions [ 8 – 10 ].”
MethodSelf-citationTadić, V., Prell, T., Lautenschläger, J., & Großkreutz, J. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00147 · Cited by 115 · see citing works
“Mutant VCP also impact mitochondria, such as via a decrease in ATP production related to mitochondrial uncoupling (Bartolome et al., 2013).”
BackgroundDisease-modifying therapies in amyotrophic lateral sclerosis
Chiò, A., Mazzini, L., & Mora, G. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.107986 · Cited by 114 · see citing works
Self-citationRoss, J. M., Olson, L., & Coppotelli, G. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160819458 · Cited by 109 · see citing works
“membrane potential and to increase mitochondrial oxygen consumption leading to mitochondrial damage and cell death both in yeast and human-derived fibroblasts [60,61].”
BackgroundThe genetics of amyotrophic lateral sclerosis: current insights
Kirby, J., Sultan, A. A., Waller, R., & Heath, P. R. (2016) · Degenerative Neurological and Neuromuscular Disease · doi:10.2147/dnnd.s84956 · Cited by 107 · see citing works
Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis
Allen, S. P., Hall, B., Castelli, L. M., Francis, L. I., Woof, R., Siskos, A., Kouloura, E., Gray, E., Thompson, A. G., Talbot, K., et al. (2019) · Brain · doi:10.1093/brain/awy353 · Cited by 102 · see citing works
“Increased reactive oxygen species production, lipid peroxidation, mitochondrial uncoupling and membrane depolarization can lead to electron transport chain (ETC) dysfunction, alterations in calcium buffering and reduced ATP generation in both the CNS and in peripheral tissues (Ferraiuolo et al., 2011b; Bartolome et al…”
BackgroundAgeing as a risk factor for ALS/FTD
Niccoli, T., Partridge, L., & Isaacs, A. M. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx247 · Cited by 102 · see citing works
Obrador, E., Palmer, R. S., López‐Blanch, R., Jihad-Jebbar, A., Vallés, S. L., & Estrela, J. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126352 · Cited by 104 · see citing works
“It has also been reported that VCP deficiency causes significant mitochondrial uncoupling, leading to decreased mitochondrial membrane potential, increased mitochondrial oxygen consumption and reduction in cellular ATP production [98].”
BackgroundClinical, pathological and functional characterization of riboflavin-responsive neuropathy
Manole, A., Jaunmuktane, Z., Hargreaves, I. P., Ludtmann, M. H. R., Salpietro, V., Bello, O. D., Pope, S. A. S., Pandraud, A., Horga, A., Scalco, R., et al. (2017) · Brain · doi:10.1093/brain/awx231 · Cited by 97 · see citing works
“…perturbations causing alteration of the ETC and increased oxidative stress are thought to be involved in the pathomechanisms of neurodegeneration in some motor neuron diseases such as ALS or spinal muscular atrophy (Johnson et al., 2010; Cozzolino and Carri, 2012; Bartolome et al., 2013).”
BackgroundSelf-citationPathogenesis/genetics of frontotemporal dementia and how it relates to ALS
Callister, J. B., & Pickering-Brown, S. M. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.06.001 · Cited by 96 · see citing works
Su, X., Broach, J. R., Connor, J. R., Gerhard, G. S., & Simmons, Z. (2014) · Muscle & Nerve · doi:10.1002/mus.24198 · Cited by 93 · see citing works
C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis
Allen, S. P., Hall, B., Woof, R., Francis, L. I., Gatto, N., Shaw, A. C., Myszczynska, M. A., Hemingway, J., Coldicott, I., Willcock, A., et al. (2019) · Brain · doi:10.1093/brain/awz302 · Cited by 89 · see citing works
The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system
Saha, I., Yuste‐Checa, P., Padilha, M. D. S., Guo, Q., Körner, R., Holthusen, H., Trinkaus, V. A., Dudanova, I., Fernández‐Busnadiego, R., Baumeister, W. P., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36058-2 · Cited by 86 · see citing works
Doa1 targets ubiquitinated substrates for mitochondria-associated degradation
Wu, X., Li, L., & Jiang, H. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201510098 · Cited by 87 · see citing works
Mitochondrial membrane potential and compartmentalized signaling: Calcium, ROS, and beyond
Selim, N. A., & Wojtovich, A. P. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103859 · Cited by 92 · see citing works
“Similarly, mutations in genes that alter mitochondrial uncoupling are tied to diseases like frontotemporal dementia and amyotrophic lateral sclerosis [15].”
Allen, S. P., Rajan, S. S., Duffy, L., Mortiboys, H., Higginbottom, A., Grierson, A. J., & Shaw, P. J. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.11.025 · Cited by 83 · see citing works
“Recently, is has been shown that mutations in the valosin containing protein lead to a loss of the mitochondrial membrane potential, a decrease in the NADH redox index and a loss of ATP production in ALS patient fibroblasts (Bartolome et al., 2013).”
Zhang, T., Mishra, P., Hay, B. A., Chan, D. C., & Guo, M. (2017) · eLife · doi:10.7554/elife.17834 · Cited by 84 · see citing works
“However, other cell-based studies suggest they behave in a dominant negative fashion (Ritz et al., 2011; Ju et al., 2009; Kim et al., 2013; Bartolome et al., 2013; Kimura et al., 2013).”
BackgroundInfluentialLudtmann, M. H. R., Kostić, M., Horne, A., Gandhi, S., Sekler, I., & Abramov, A. Y. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1469-5 · Cited by 83 · see citing works
Self-citationPeripheral Glycolysis in Neurodegenerative Diseases
Bell, S., Burgess, T., Lee, J., Blackburn, D. J., Allen, S. P., & Mortiboys, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238924 · Cited by 83 · see citing works
Maria Jose Perez, J., Ponce, D. P., Osorio‐Fuentealba, C., Behrens, M. I., & Quintanilla, R. A. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00553 · Cited by 80 · see citing works
“In fact, there are several examples of using skin fibroblasts to study metabolic abnormalities related to neurological (Zoumakis et al., 2007), psychiatric (Kalman et al., 2016), neurometabolic (Khan and Alkon, 2015) and neurodegenerative diseases (Lopez-Erauskin et al., 2012; Ambrosi et al., 2014), in particular Hunt…”
BackgroundBartolomé, F. B., de la Cueva, M., Pascual, C., Antequera, D., Fernández, T., Gil, C., Martı́nez, A., & Carro, E. (2018) · Alzheimer s Research & Therapy · doi:10.1186/s13195-018-0352-4 · Cited by 78 · see citing works
“onal cultures were prepared from rat embryos (E15–16) based on methods previously described [32], and 4 × 10(5) cells per well were plated on poly-L-lysine-coated cover-”
MethodYaron, A., & Schuldiner, O. (2016) · Current Biology · doi:10.1016/j.cub.2016.05.025 · Cited by 76 · see citing works
Mitochondrial Dysfunction in Neuromuscular Disorders
Katsetos, C. D., Koutzaki, S. H., & Melvin, J. J. (2013) · Seminars in Pediatric Neurology · doi:10.1016/j.spen.2013.10.010 · Cited by 75 · see citing works
Singh, G., Passari, A. K., Singh, P., Leo, V. V., Sarathbabu, S., Kumar, B., Singh, B. P., Lalhlenmawia, H., & Kumar, N. S. (2017) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-017-2000-0 · Cited by 75 · see citing works
“The pharmaceutical property of the plant seems to be associated with the bioactive phytochemical compounds, especially sesquiterpene lactones and polyacetylenes, which inhibit the growth of pathogenic microorganisms and the flavonoids, which are considered as effective antiinflammatory agents [6, 11, 12].”
BackgroundMolecular Genetics of Neurodegenerative DementiasPreprint
Hinz, F. I., & Geschwind, D. H. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a023705 · Cited by 74 · see citing works
“Deficiency in VCP in neurons leads to mitochondrial uncoupling and significant reduction of cellular ATP production (Bartolome et al. 2013).”
BackgroundBartolomé, F. B., Esteras, N., Martín‐Requero, Á., Boutoleau‐Bretonnière, C., Vercelletto, M., Gabelle, A., Ber, I. L., Honda, T., Dinkova‐Kostova, A. T., Hardy, J., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-01678-4 · Cited by 66 · see citing works
Self-citationWang, T., Xu, W., Qin, M., Yang, Y. A., Bao, P., Shen, F., Zhang, Z., & Xu, J. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.729343 · Cited by 65 · see citing works
“Although some of the pathogenic VCP mutations have been shown to affect the ATPase activities (11, 12) or mitochondrial function (13, 14), the effects of these mutations in protein homeostasis, especially in the cellular stress response associated with the development of degenerative diseases, are unclear.”
BackgroundChu, S., Xie, X., Payan, C., & Stochaj, U. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00639-y · Cited by 58 · see citing works
“Mitochondrial abnormalities linked to mutant VCP include elevated reactive oxygen species (ROS) levels, mitochondrial uncoupling, reduced ATP production, mitochondrial fusion defects, and impaired clearance of damaged mitochondria [50, 114, 173, 174].”
BackgroundMartin, L. J., Fancelli, D., Wong, M., Niedzwiecki, M. V., Ballarini, M., Plyte, S. E., & Chang, Q. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00433 · Cited by 63 · see citing works
“Other studies support the role of mitochondrial calcium dysregulation and mPTP activation in the mechanisms of ALS (Bendotti et al., 2001; Jaiswal and Keller, 2009; Barrientos et al., 2011; Nguyen et al., 2011; Bartolome et al., 2013; Muyderman and Chen, 2014).”
Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease
Ambrosi, G., Ghezzi, C., Sepe, S., Milanese, C., Payán‐Gómez, C., Bombardieri, C. R., Armentero, M., Zangaglia, R., Pacchetti, C., Mastroberardino, P. G., et al. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.05.008 · Cited by 59 · see citing works
Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum
Shahheydari, H., Ragagnin, A., Walker, A. K., Toth, R. P., Vidal, M., Jagaraj, C. J., Perri, E. R., Konopka, A., Sultana, J. M., & Atkin, J. D. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00119 · Cited by 59 · see citing works
“…in vitro (Halawani et al., 2009) and in Drosophila (Manno et al., 2010; Chan et al., 2012), leading to disruption of mitochondrial bioenergetics (Bartolome et al., 2013) and can alter the conformation and binding of co-factors ubiquitin ligase E4B and ataxin 3 (Fernández-Sáiz and Buchberger,…”
BackgroundMultifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia
Ranganathan, R., Haque, S., Coley, K., Shepheard, S. R., Cooper‐Knock, J., & Kirby, J. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00684 · Cited by 59 · see citing works
Chen, J., Bassot, A., Giuliani, F., & Simmen, T. (2021) · Cells · doi:10.3390/cells10071789 · Cited by 57 · see citing works
“Moreover, the mutation of VCP is expected to disrupt the control of OXPHOS normally maintained by Ca2+ and ROS signaling on MERCs, an observation that is indeed made in patient fibroblasts [163].”
BackgroundThe Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis—Frontotemporal Dementia
Scarian, E., Fiamingo, G., Diamanti, L., Palmieri, I., Gagliardi, S., & Pansarasa, O. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.841394 · Cited by 54 · see citing works
“The uncoupling results in a reduction in ATP production and consequently in a more vulnerable state of the cells (176, 177).”
BackgroundUBXD8 mediates mitochondria‐associated degradation to restrain apoptosis and mitophagy
Zheng, J., Cao, Y., Yang, J., & Jiang, H. (2022) · EMBO Reports · doi:10.15252/embr.202254859 · Cited by 52 · see citing works
“Mitochondrial damage and functional impairment are prominent in VCP-mutant organisms including yeast, drosophila, mouse, and human (Braun et al , 2006; Custer et al , 2010; Chang et al , 2011; Yin et al , 2012; Bartolome et al , 2013; Kim et al , 2013; Ludtmann et al , 2017; Zhang et al , 2017).”
Magnetic resonance spectroscopy reveals mitochondrial dysfunction in amyotrophic lateral sclerosis
Sassani, M., Alix, J. J. P., McDermott, C. J., Baster, K., Hoggard, N., Wild, J. M., Mortiboys, H., Shaw, P. J., Wilkinson, I. D., & Jenkins, T. M. (2020) · Brain · doi:10.1093/brain/awaa340 · Cited by 51 · see citing works
Create and preserve: Proteostasis in development and aging is governed by Cdc48/p97/VCP
Franz, A., Ackermann, L., & Hoppe, T. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.03.031 · Cited by 49 · see citing works
“[178] suggests that the decrease in cellular ATP levels is a result of mitochondrial dysfunction.”
BackgroundWang, Z.-H., Clark, C. P., & Geisbrecht, E. R. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw067 · Cited by 44 · see citing works
Sun, X., & Qiu, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113842 · Cited by 42 · see citing works
“Interestingly, most disease-associated VCP mutations are found in the N-domains and ATPase domains [22], and those mutations in VCP have been shown to impair mitochondrial function and protein homeostasis [23,24].”
BackgroundGuo, X. L., & Qi, X. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.11.026 · Cited by 43 · see citing works
Kimura, Y., Fukushi, J., Hori, S., Matsuda, N., Okatsu, K., Kakiyama, Y., Kawawaki, J., Kakizuka, A., & Tanaka, K. (2013) · Genes to Cells · doi:10.1111/gtc.12103 · Cited by 41 · see citing works
Larrea, D., Tamucci, K. A., Kabra, K., VELASCO, K. R., Yun, T. D., Pera, M., Montesinos, J., Agrawal, R. R., Paradas, C., Smerdon, J. W., et al. (2025) · Nature Communications · doi:10.1038/s41467-024-51578-1 · Cited by 39 · see citing works
“Multiple reports have implicated SOD1 as a mediator of the mitochondrial disturbances in the disease, both when it is mutated in fALS and when it is misfolded in sALS 32,33 .”
Visualization of mitochondrial membrane potential in mammalian cells
Esteras, N., Adjobo-Hermans, M. J. W., Abramov, A. Y., & Koopman, W. J. H. (2019) · Methods in cell biology · doi:10.1016/bs.mcb.2019.10.003 · Cited by 39 · see citing works
Self-citationLudtmann, M. H. R., Arber, C., Bartolomé, F. B., de Vicente, M., Preza, E., Carro, E., Houlden, H., Gandhi, S., Wray, S., & Abramov, A. Y. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.762898 · Cited by 39 · see citing works
“Our previous study provided evidence of lower ATP levels as well as uncoupled mitochondria (4).”
BackgroundResultInfluentialSelf-citationPrajapati, P., Sripada, L., Singh, K., Roy, M., Bhatelia, K., Dalwadi, P., & Singh, R. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0664-6 · Cited by 36 · see citing works
Jagaraj, C. J., Parakh, S., & Atkin, J. D. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.581950 · Cited by 36 · see citing works
“Similarly, abnormal accumulation and aggregation of mitochondria in the inter-myofibrillar space was detected in iPSCs derived from an ALS patient bearing a VCP mutation (Bartolome et al., 2013; Hall et al., 2017).”
BackgroundZiff, O. J., Harley, J., Wang, Y., Neeves, J., Tyzack, G. E., Ibrahim, F., Skehel, M. J., Chakrabarti, A. M., Kelly, G. P., & Patani, R. (2023) · Neuron · doi:10.1016/j.neuron.2023.06.019 · Cited by 36 · see citing works
Anderson, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010587 · Cited by 36 · see citing works
Anton, A., Mazeaud, C., Freppel, W., Gilbert, C., Tremblay, N., Sow, A. A., Roy, M., Rodrigue‐Gervais, I. G., & Chatel‐Chaix, L. (2021) · Cellular Microbiology · doi:10.1111/cmi.13302 · Cited by 31 · see citing works
“VCP has also important functions in autophagy-associated mitochondrial morphology and oxidative respiration (Bartolome et al., 2013; Guo et al., 2016; Kim et al., 2013; Ludtmann et al., 2017; Zhang, Mishra, Hay, Chan, & Guo, 2017), two features modulated by DENV and/or ZIKV (Barbier et al., 2017;…”
BackgroundDistinction of sporadic and familial forms of ALS based on mitochondrial characteristics
Walczak, J., Dębska–Vielhaber, G., Vielhaber, S., Szymański, J., Charzyńska, A., Duszyński, J., & Szczepanowska, J. (2018) · The FASEB Journal · doi:10.1096/fj.201801843r · Cited by 33 · see citing works
“(71) suggests that in ALS fibroblasts carrying amutation in theVCP gene, changes inATP level might be caused by ATP synthase working in its reverse mode—hydrolyzing ATP in order to maintain the DCm.”
BackgroundSreedharan, J., Blakeney, I., & Brown, R. H. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-813866-3.00020-5 · Cited by 32 · see citing works
Pontifex, C. S., Zaman, M., Fanganiello, R. D., Shutt, T. E., & Pfeffer, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115633 · Cited by 33 · see citing works
“Furthermore, this group was able to demonstrate that ZFAND1 specifically supports stress granule degradation via the proteasome, and, when ZFAND1 was depleted, stress granules were instead cleared away by the autophagy system [108].”
BackgroundNitric oxide-targeted protein phosphorylation during human sperm capacitation
Staicu, F.-D., Martínez-Soto, J. C., Cánovas, S., & Matás, C. (2021) · Scientific Reports · doi:10.1038/s41598-021-00494-1 · Cited by 31 · see citing works
Crosstalk Between Oxidative Stress and Mitochondrial Damage: Focus on Amyotrophic Lateral Sclerosis
Greco, V., Longone, P., Spalloni, A., Pieroni, L., & Urbani, A. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-8367-0_5 · Cited by 29 · see citing works
Nalbandian, A., Llewellyn, K. J., Gómez, A. E., Walker, N., Su, H., Dunnigan, A., Chwa, M., Vesa, J., Kenney, M. C., & Kimonis, V. E. (2015) · Mitochondrion · doi:10.1016/j.mito.2015.02.004 · Cited by 30 · see citing works
“Our findings are in accordance with a previously reported study by Bartolome et al. (2013) illustrating low membrane potential and ATP levels in VCP deficient cells (Bartolome et al., 2013).”
BackgroundResultLizano, P. L., Rashed, E. R., Stoll, S., Zhou, N., Wen, H., Hays, T. T., Qin, G., Xie, L., Depré, C., & Qiu, H. (2017) · Scientific Reports · doi:10.1038/srep46324 · Cited by 30 · see citing works
Harley, J., Hagemann, C., Serio, A., & Patani, R. (2021) · Brain Communications · doi:10.1093/braincomms/fcab166 · Cited by 28 · see citing works
Defects of Nutrient Signaling and Autophagy in Neurodegeneration
Ondaro, J., Hernández-Eguiazu, H., Garciandia-Arcelus, M., Loera‐Valencia, R., Rodríguez-Gómez, L., Jiménez-Zúñiga, A., Goikolea, J., Rodriguez‐Rodriguez, P., Ruiz‐Martínez, J., Moreno, F., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.836196 · Cited by 27 · see citing works
The aging of ER-mitochondria communication: A journey from undifferentiated to aged cells
Morgado-Cáceres, P., Liabeuf, G., Calle, X., Briones, L., Riquelme, J. A., Bravo, R., & Parra, V. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.946678 · Cited by 26 · see citing works
“VCP disrupts the control of OXPHOS normally maintained by Ca and ROS signaling on MERCs, as observed in ALS patient fibroblasts (Bartolome et al., 2013).”
BackgroundA network of RNA and protein interactions in Fronto Temporal Dementia
Fontana, F., Siva, K., & Denti, M. A. (2015) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2015.00009 · Cited by 27 · see citing works
“…VCP mutations, VCP-deficient cells, mouse cortical primary neurons and astrocytes, to conclude that reduction of VCP led to uncoupling of mitochondria and increased oxygen consumption and a subsequent decrease in ATP of cells leading to cellular toxicity and neuronal death (Bartolome et al., 2013).”
BackgroundAzithromycin Affords Neuroprotection in Rat Undergone Transient Focal Cerebral Ischemia
Amantea, D., Petrelli, F., Greco, R., Tassorelli, C., Corasaniti, M. T., Tonin, P., & Bagetta, G. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01256 · Cited by 25 · see citing works
Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion
Escobar‐Henriques, M., & Anton, V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186841 · Cited by 25 · see citing works
Codron, P., Cassereau, J., Vourc’h, P., Veyrat‐Durebex, C., Blasco, H., Kane, M. S., Procaccio, V., Letournel, F., Verny, C., Lenaers, G., et al. (2018) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2018.1431787 · Cited by 25 · see citing works
Peng, Y., Zhou, L., Jin, Y., Wu, D., Chen, N., Zhang, C., Liu, H., Li, C., Ning, R., Yang, X., et al. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-00630 · Cited by 24 · see citing works
“…from patients with ALS, VCP defects can lead to severe mitochondrial uncoupling, a decrease in mitochondrial membrane potential, and an increase in mitochondrial oxygen consumption, destroying oxidative phosphorylation normally maintained by Ca 2+ and ROS signaling on MAMs (Bartolome et al., 2013).”
Llewellyn, K. J., Nalbandian, A., Jung, K., Nguyen, C., Avanesian, A., Mozaffar, T., Piomelli, D., & Kimonis, V. E. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt523 · Cited by 24 · see citing works
“VCP plays a critical role in maintaining mitochondrial quality and dynamics in the PINK1/Parkin pathway, whereby pathogenic mutations in VCP lead to an impairment in proteasome-dependent degradation (22) and induce mitochondrial uncoupling and reduced ATP levels in human neuroblastoma cells (23).”
BackgroundRodríguez-Periñán, G., de la Encarnación, A., Moreno, F., de Munaín, A. L., Martı́nez, A., Martín‐Requero, Á., Alquézar, C., & Bartolomé, F. B. (2023) · Antioxidants · doi:10.3390/antiox12030581 · Cited by 23 · see citing works
“Measurement of Mitochondrial Membrane Potential (∆Ψm) Mitochondrial membrane potential (∆Ψm) was analyzed using the cell-permeant fluorescent dyes tetramethylrhodamine ethyl ester (TMRE, Thermo Fisher Scientific, MA, USA) and tetramethylrhodamine methyl ester (TMRM, Thermo Fisher Scientific, MA, USA), according to pre…”
MethodWu, K., Liu, J., Zhuang, N., & Wang, T. (2014) · The FASEB Journal · doi:10.1096/fj.14-255802 · Cited by 23 · see citing works
“Mitochondrial uncoupling is associated with a variety of neurodegenerative conditions, depriving neurons of essential energy and making them more vulnerable to stressful conditions (32).”
BackgroundParé, B., & Gros‐Louis, F. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0004 · Cited by 22 · see citing works
“Interestingly, VCP mutations are also associated with the development of multisystem proteinopathy, which can lead to ALS, FTD, Paget disease, Parkinson’s disease, and myopathy via defects in the mitochondrial dynamics (Bartolome et al., 2013; Benatar et al., 2013; Kim et al., 2013).”
BackgroundCRISPR/Cas9-engineered Drosophila knock-in models to study VCP diseases
Wall, J. M., Basu, A., Zunica, E. R. M., Dubuisson, O. S., Belmont, K. P., Broussard, J. P., Kirwan, J. P., Axelrod, C. L., & Johnson, A. E. (2021) · Disease Models & Mechanisms · doi:10.1242/dmm.048603 · Cited by 19 · see citing works
“Substrate and sex-specific defects in mitochondrial respiratory function in VCP mutants Cells expressing pathogenic VCP mutations exhibit reduced ATP levels (Chang et al., 2011; Bartolome et al., 2013), perhaps due to compromised mitochondrial respiration and/or failure to clear damaged mitochondria, which could contr…”
BackgroundZanini, G., Selleri, V., Nasi, M., Gaetano, A. D., Martinelli, I., Gianferrari, G., Lofaro, F. D., Boraldi, F., Mandrioli, J., & Pinti, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911881 · Cited by 21 · see citing works
“Proteomic analysis revealed a profound alteration in the relative levels of proteins related to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation system (OXPHOS), suggesting that an enhanced localization of a mutated form of TDP-43 in the mitochondria leads to an imbalance of the biological processes cr…”
BackgroundSelf-citationRare Manifestation of a c.290 C>T, p.Gly97Glu VCP Mutation
Jerath, N. U., Crockett, C. D., Moore, S. A., Shy, M. E., Weihl, C. C., Chou, T., Grider, T., Gonzalez, M., Zuchner, S. L., & Swenson, A. (2015) · Case Reports in Genetics · doi:10.1155/2015/239167 · Cited by 21 · see citing works
Pérez‐Siles, G., Ly, C., Grant, A. J., Drew, A. P., Yiu, E. M., Ryan, M. M., Chuang, D., Tso, S.-C., Nicholson, G. A., & Kennerson, M. L. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.07.001 · Cited by 19 · see citing works
“Other CMT genemutations reporting mitochondrial bioenergetic deficits of reduced ATP levels include COX6A1 (Tamiya et al., 2014), DHTKD1 (Xu et al., 2012), VCP (Gonzalez et al., 2014) (Bartolome et al., 2013) and MT-ATP6 (Pitceathly et al., 2012).”
Mao, Y., Kuo, S.-W., Chen, L., Heckman, C. J., & Jiang, M. C. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172246 · Cited by 19 · see citing works
Mitochondrial dysfunction and energy deprivation in the mechanism of neurodegeneration
Abramov, A. Y., & Angelova, P. R. (2019) · Turkish Journal of Biochemistry · doi:10.1515/tjb-2019-0255 · Cited by 18 · see citing works
“In the cells with familial forms of neurodegenerative disorders, such as motoneuron disease (VCP) or parkinsonism (HTRA2 deficiency) profound mitochondrial uncoupling lead to the lack of ATP and neuronal loss [11, 12].”
BackgroundSelf-citationFTLD Patient–Derived Fibroblasts Show Defective Mitochondrial Function and Accumulation of p62
Leskelä, S., Hoffmann, D. B., Rostalski, H., Huber, N., Wittrahm, R., Hartikainen, P. H., Korhonen, V. E., Leinonen, V., Hiltunen, M. O., Solje, E., et al. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02475-x · Cited by 16 · see citing works
“A382T) genes [60, 61]; and ALS and FTLD patients carrying the C9-HRE [62].”
BackgroundNeurons undergo pathogenic metabolic reprogramming in models of familial ALS
Riechers, S., Mojsilovic‐Petrovic, J., Belton, T. B., Chakrabarty, R. P., Garjani, M., Medvedeva, V., Dalton, C., Wong, Y. C., Chandel, N. S., Dienel, G. A., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101468 · Cited by 16 · see citing works
Rab-dependent cellular trafficking and amyotrophic lateral sclerosis
Parakh, S., Perri, E. R., Jagaraj, C. J., Ragagnin, A., & Atkin, J. D. (2018) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2018.1553926 · Cited by 15 · see citing works
“Similarly, VCP mutant mice display abnormal aggregated mitochondria (Yin et al. 2012; Nalbandian et al. 2013) and deficiency of VCP results in reduced mitochondrial membrane potential, increased oxygen consumption and reduced ATP production in cellular models (Bartolome et al. 2013).”
BackgroundMolecular pathways of mitochondrial outer membrane protein degradation
Zheng, J., Li, L., & Jiang, H. (2019) · Biochemical Society Transactions · doi:10.1042/bst20190275 · Cited by 13 · see citing works
Targeting Mitochondrial Metal Dyshomeostasis for the Treatment of Neurodegeneration
Liddell, J. R. (2015) · Neurodegenerative Disease Management · doi:10.2217/nmt.15.19 · Cited by 13 · see citing works
“Following the discovery of mutations in SOD1 in 1993 [93], a growing number of genes have been associated with the 5-10% of familial ALS cases [94], including TAR DNA binding protein 43 (TDP-43), fused in sarcoma (FUS) and valosin-containing protein (VCP), while the causes of sporadic ALS are yet to be utilising SOD1…”
BackgroundLlewellyn, K. J., Nalbandian, A., Weiss, L. N., Chang, I. W.-C., Yu, H., Khatib, B., Tan, B., Scarfone, V. M., & Kimonis, V. E. (2017) · PLoS ONE · doi:10.1371/journal.pone.0176919 · Cited by 13 · see citing works
RetractedThe Underestimated Role of Iron in Frontotemporal Dementia: A Narrative Review
Ferretti, S., & Zanella, I. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312987 · Cited by 12 · see citing works
- Authors
- Bartolome, F., Wu, H.-C., Burchell, V. S., Preza, E., Wray, S., Mahoney, C. J., Fox, N. C., Calvo, A., Canosa, A., Moglia, C., Mandrioli, J., Chiò, A., Orrell, R. W., Houlden, H., Hardy, J., Abramov, A. Y., & Plun-Favreau, H.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- University of Turin (IT)
- University of Modena and Reggio Emilia (IT)
- National Hospital for Neurology and Neurosurgery (GB)
- Corresponding author
- Abramov, Andrey Y.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 78
- Issue
- 1
- Pages
- 57-64
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3843114
- OpenAlex
- W2143472860
- Cited by
- 156
- References
- 40
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 10 · 2023: 8 · 2022: 11 · 2021: 15 · 2020: 11 · 2019: 11 · 2018: 7 · 2017: 21 · 2016: 13 · 2015: 14 · 2014: 11 · 2013: 9
- FWCI
- 7.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (FP7/2007–2013, WT089698, 089698)
- National Institute for Health and Care Research (FP7/2007–2013)
- University College London
- Fundación Española para la Ciencia y la Tecnología
- Medical Research Council (FP7/20072013, 259867, MC_G1000735, MR/J004758/1, WT089698, MR/K000608/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- VCP, VCP mutations, mitochondrial uncoupling, mitochondrial membrane potential, mitochondrial oxygen consumption, ATP production, energy metabolism, ischemia, cell death, inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, amyotrophic lateral sclerosis, fibroblasts
- MeSH terms
- Valosin Containing Protein, Adenosine Triphosphatases, Adenosine Triphosphate, Adult, Aged, Analysis of Variance, Animals, Animals, Newborn, Cells, Cultured, Cerebral Cortex, Family Health, Female, Fibroblasts, Humans, Luminescent Proteins, Magnesium, Male, Mice, Inbred C57BL, Middle Aged, Mitochondria, Mutation, NAD, Neuroblastoma, Neurons, Osteitis Deformans, Oxygen Consumption, Transfection, Lipid Peroxidation, Case-Control Studies, Cell Cycle Proteins, Myositis, Inclusion Body, RNA, Small Interfering, Muscular Dystrophies, Limb-Girdle, Mice, Membrane Potential, Mitochondrial, Frontotemporal Dementia
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