Mitochondria, motor neurons and aging
Abstract
While the role of mitochondria in aging has been well characterized, their involvement in motor neuron aging remains poorly understood. Thus, we performed an exhaustive ultrastructural study of mitochondria in motor neurons from aged rats that revealed dramatic alterations in the mitochondria of axon terminals at neuromuscular junctions, characterized by swelling, mitochondrial fusion and the presence of megamitochondria. These alterations were not observed in ventral horn motor neurons in the spinal cord of aged rats, which were only altered by the appearance of electron-dense bodies in the dilated matrix cristae. Using X-ray microanalytical techniques we demonstrated the presence of calcium in these bodies, suggesting Ca(2+) overload. Moreover, in motor neurons from aged rats, cytochrome c and activated caspase 3 were detected in the cytoplasm of axon terminals at neuromuscular junctions, factors implicated in the apoptosis. Active caspase 3 was also found in the nucleus, soma and axons of aged alpha motor neuron neurons, where it mainly associated with microtubules. The colocalization of dynein and cleaved caspase 3 in neuromuscular junctions is strongly suggestive of the retrograde transport of apoptotic factors to the soma. These results are consistent with the early stages of degeneration in neuromuscular junctions during aging, which is followed by dying back. Given that aging is a key risk factor for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), the identification of age-related motor neuron degeneration initiated at the distal end of the axon may provide a new therapeutic target for early intervention.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The same mitochondrial-induced initiation of apoptosis signaling that occurs in skeletal muscle also occurs in neuromuscular junctions with aging.
“Together, these observations confirm that the same mitochondrial-induced initiation of apoptosis signaling that occurs in skeletal muscle also occurs in neuromuscular junctions with aging.”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [39]
Dysfunction of mitochondrial metabolism and dynamics contributes to elevations in cytosolic cytochrome c and caspase-3 at the neuromuscular junction.
“The resulting dysfunction of mitochondrial metabolism and dynamics contributes to elevations in cytosolic cytochrome c and caspase-3 (39).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [39]
In aging rats, mitochondria in axon terminals of the neuromuscular junction undergo swelling partly from calcium overload.
“Observations from aging rats suggests that mitochondria in the axon terminals of the neuromuscular junction undergo swelling, in part from calcium overload.”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [39]
Cites
Green, D. R., & Reed, J. C. (1998) · Science · doi:10.1126/science.281.5381.1309 · Cited by 8,998 · see citing works
Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455 · see citing works
Wallace, D. C. (2005) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.110304.095751 · Cited by 3,185 · see citing works
Mitochondrial control of cell death
Kroemer, G., & Reed, J. C. (2000) · Nature Medicine · doi:10.1038/74994 · Cited by 3,103 · see citing works
Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man
Fischer, L. R., Culver, D. G., Tennant, P., Davis, A. A., Wang, M.-S., Castellano-Sanchez, A. A., Khan, J., Polak, M. A., & Glass, J. D. (2004) · Experimental Neurology · doi:10.1016/j.expneurol.2003.10.004 · Cited by 1,338 · see citing works
Autoactivation of Procaspase-9 by Apaf-1-Mediated Oligomerization
Srinivasula, S. M., Ahmad, M., Fernandes‐Alnemri, T., & Alnemri, E. S. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80095-7 · Cited by 1,119 · see citing works
Reddy, P. H., & Beal, M. F. (2008) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.12.002 · Cited by 975 · see citing works
Mutant dynactin in motor neuron disease
Puls, I., Jonnakuty, C., LaMonte, B. H., Holzbaur, E. L. F., Tokito, M. K., MANN, E. A., Floeter, M. K., Bidus, K., Drayna, D. T., Oh, S. J., et al. (2003) · Nature Genetics · doi:10.1038/ng1123 · Cited by 961 · see citing works
Mitochondria take center stage in aging and neurodegeneration
Beal, M. F. (2005) · Annals of Neurology · doi:10.1002/ana.20624 · Cited by 957 · see citing works
Three-Dimensional Structure of the Apoptosome
Acehan, D., Jiang, X., Morgan, D. G., Heuser, J. E., Wang, X., & Akey, C. W. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00442-2 · Cited by 912 · see citing works
Beckman, J. S., Carson, M. A., Smith, C. D. L., & Koppenol, W. H. (1993) · Nature · doi:10.1038/364584a0 · Cited by 876 · see citing works
Apoptosis and Caspases in Neurodegenerative Diseases
Friedlander, R. M. (2003) · New England Journal of Medicine · doi:10.1056/nejmra022366 · Cited by 873 · see citing works
Altered Reactivity of Superoxide Dismutase in Familial Amyotrophic Lateral Sclerosis
Wiedau‐Pazos, M., Goto, J. J., Rabizadeh, S., Gralla, E. B., Roe, J. A., Lee, M. K., Valentine, J. S., & Bredesen, D. E. (1996) · Science · doi:10.1126/science.271.5248.515 · Cited by 720 · see citing works
Functional Role of Caspase-1 and Caspase-3 in an ALS Transgenic Mouse Model
Li, M., Ona, V. O., Guégan, C., Chen, M., Jackson-Lewis, V. R., Andrews, L. J., Olszewski, A. J., Stieg, P. E., Lee, J.-P., Przedborski, S., et al. (2000) · Science · doi:10.1126/science.288.5464.335 · Cited by 717 · see citing works
Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport
Hafezparast, M., Klocke, R., Ruhrberg, C., Marquardt, A., Ahmad‐Annuar, A., Bowen, S., Lalli, G., Witherden, A. S., Hummerich, H., Nicholson, S. J., et al. (2003) · Science · doi:10.1126/science.1083129 · Cited by 684 · see citing works
Frey, D., Schneider, C., Xu, L., Borg, J., Spooren, W. P. J. M., & Caroni, P. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-07-02534.2000 · Cited by 683 · see citing works
Mitochondrial bioenergetics and structural network organization
Benard, G., Bellance, N., James, D., Parrone, P., Fernandez, H., Letellier, T., & Rossignol, R. (2007) · Journal of Cell Science · doi:10.1242/jcs.03381 · Cited by 618 · see citing works
Estévez, A. G., Crow, J. P., Sampson, J. B., Reiter, C., Zhuang, Y., Richardson, G. J., Tarpey, M. M., Barbeito, L., & Beckman, J. S. (1999) · Science · doi:10.1126/science.286.5449.2498 · Cited by 596 · see citing works
Caspase-9 and APAF-1 form an active holoenzymePreprint
Rodriguez, J., & Lazebnik, Y. A. (1999) · Genes & Development · doi:10.1101/gad.13.24.3179 · Cited by 573 · see citing works
LaMonte, B. H., Wallace, K. E., Holloway, B. A., Shelly, S. S., Ascaño, J., Tokito, M. K., Winkle, T. V., Howland, D., & Holzbaur, E. L. F. (2002) · Neuron · doi:10.1016/s0896-6273(02)00696-7 · Cited by 540 · see citing works
Role of AIF in caspase-dependent and caspase-independent cell death
Cregan, S. P., Dawson, V. L., & Slack, R. S. (2004) · Oncogene · doi:10.1038/sj.onc.1207517 · Cited by 520 · see citing works
Role of cytochrome c and dATP/ATP hydrolysis in Apaf‐1‐mediated caspase‐9 activation and apoptosis
Hu, Y., Benedict, M. A., Ding, L., et al. (1999) · The EMBO Journal · doi:10.1093/emboj/18.13.3586 · Cited by 454 · see citing works
Fzo1, a Protein Involved in Mitochondrial Fusion, Inhibits Apoptosis
Sugioka, R., Shimizu, S., & Tsujimoto, Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408910200 · Cited by 341 · see citing works
Hegedus, J., Putman, C. T., & Gordon, T. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.07.003 · Cited by 320 · see citing works
Neuspiel, M., Zunino, R., Gangaraju, S., Rippstein, P. U., & McBride, H. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501599200 · Cited by 308 · see citing works
Synaptic Mitochondria Are More Susceptible to Ca2+Overload than Nonsynaptic Mitochondria
Brown, M. R., Sullivan, P. G., & Geddes, J. W. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m510303200 · Cited by 297 · see citing works
Jang, Y. C., Lustgarten, M. S., Liu, Y., Müller, F. L., Bhattacharya, A., Liang, H., Salmon, A. B., Brooks, S. V., Larkin, L. M., Hayworth, C. R., et al. (2009) · The FASEB Journal · doi:10.1096/fj.09-146308 · Cited by 290 · see citing works
Yoon, Y., Yoon, D., Lim, I. K., Yoon, S., Chung, H., Rojo, M., Malka, F., Jou, M., Martinou, J., & Yoon, G. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20753 · Cited by 275 · see citing works
Mitochondrial Medicine for Aging and Neurodegenerative Diseases
Reddy, P. H. (2008) · NeuroMolecular Medicine · doi:10.1007/s12017-008-8044-z · Cited by 230 · see citing works
Mitochondrial dysfunction and its role in motor neuron degeneration in ALS
Manfredi, G., & Xu, Z. (2005) · Mitochondrion · doi:10.1016/j.mito.2005.01.002 · Cited by 215 · see citing works
Mitochondrial calcium function and dysfunction in the central nervous system
Nicholls, D. G. (2009) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.03.010 · Cited by 213 · see citing works
Dupuis, L., de Aguilar, J. G., Echaniz‐Laguna, A., Eschbach, J., René, F., Oudart, H., Halter, B., Huzé, C., Schaeffer, L., Bouillaud, F., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005390 · Cited by 209 · see citing works
Mitochondrial dysfunction in amyotrophic lateral sclerosis
Shi, P., Gál, J., Kwinter, D. M., Liu, X., & Zhu, H. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.08.012 · Cited by 205 · see citing works
Ca2+ Homeostasis during Mitochondrial Fragmentation and Perinuclear Clustering Induced by hFis1
Frieden, M., James, D. I., Castelbou, C., Danckaert, A., Martinou, J., & Demaurex, N. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312366200 · Cited by 203 · see citing works
Megamitochondria formation ‐ physiology and pathology
Wakabayashi, T. (2002) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2002.tb00452.x · Cited by 189 · see citing works
Reddy, P. H. (2009) · CNS Spectrums · doi:10.1017/s1092852900024901 · Cited by 186 · see citing works
Xu, W., Chi, L., Xu, R., Ke, Y., Luo, C., Cai, J., Qiu, M. S., Gozal, D., & Liu, R. (2004) · Spinal Cord · doi:10.1038/sj.sc.3101674 · Cited by 160 · see citing works
Pivovarova, N. B., Nguyen, H. V., Winters, C. A., Brantner, C. A., Smith, C. L., & Andrews, S. B. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0531-04.2004 · Cited by 146 · see citing works
Mitochondria in cybrids containing mtDNA from persons with mitochondriopathies
Swerdlow, R. H. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21167 · Cited by 128 · see citing works
Mitochondria and aging: A role for the permeability transition?
Crompton, M. (2004) · Aging Cell · doi:10.1046/j.1474-9728.2003.00073.x · Cited by 101 · see citing works
Calcium and cell death signaling in neurodegeneration and aging
Smaili, S. S., Hirata, H., Ureshino, R. P., Monteforte, P. T., Morales, A. P., Muler, M. L., Terashima, J. Y., Oseki, K., Rosenstock, T. R., Lopes, G. S., et al. (2009) · Anais da Academia Brasileira de Ciências · doi:10.1590/s0001-37652009000300011 · Cited by 79 · see citing works
Kristián, T., Pivovarova, N. B., Fiskum, G. M., & Andrews, S. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04626.x · Cited by 72 · see citing works
New insights into mitochondrial fusion
Zhang, Y., & Chan, D. C. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.01.095 · Cited by 58 · see citing works
Age‐related changes in regional brain mitochondria from Fischer 344 rats
LaFrance, R., Brustovetsky, N., Sherburne, C., DeLong, D., & Dubinsky, J. M. (2005) · Aging Cell · doi:10.1111/j.1474-9726.2005.00156.x · Cited by 51 · see citing works
Carson, C., Saleh, M., Fung, F. W., Nicholson, D. W., & Roskams, A. J. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0707-05.2005 · Cited by 51 · see citing works
Cytosolic and mitochondrial calcium in synaptosomes during aging
Satrústegui, J., Villalba, M., Pereira, R., et al. (1996) · Life Sciences · doi:10.1016/0024-3205(96)00322-0 · Cited by 49 · see citing works
Programmed cell death and apoptosis in aging and life span regulation.
Shen, J., & Tower, J. (2009) · PubMed · Cited by 35 · see citing works
Early detachment of neuromuscular junction proteins in ALS mice with SODG93A mutation
Narai, H., Manabe, Y., Nagai, M., Nagano, I., Ohta, Y., Murakami, T., Takehisa, Y., Kamiya, T., & Abe, K. (2009) · Neurology International · doi:10.4081/ni.2009.e16 · Cited by 35 · see citing works
A mathematical model of mitochondrial swelling
Eisenhofer, S., Toókos, F., Hense, B. A., et al. (2010) · BMC Research Notes · doi:10.1186/1756-0500-3-67 · Cited by 24 · see citing works
Hardt, M., & Plattner, H. (1999) · Journal of Structural Biology · doi:10.1006/jsbi.1999.4188 · Cited by 20 · see citing works
Frey, T., & Sun, M. (2008) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2008.05.011 · Cited by 19 · see citing works
Zhang, A., Lorke, D. E., Wu, S., et al. (2006) · Neurosignals · doi:10.1159/000094602 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The ageing neuromuscular system and sarcopenia: A mitochondrial perspective
Rygiel, K. A., Picard, M., & Turnbull, D. M. (2016) · The Journal of Physiology · doi:10.1113/jp271212 · Cited by 165 · see citing works
Mitochondria initiate and regulate sarcopenia
Alway, S. E., Mohamed, J. S., & Myers, M. J. (2017) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000101 · Cited by 153 · see citing works
Neuromuscular Junction Dismantling in Amyotrophic Lateral Sclerosis
Cappello, V., & Francolini, M. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102092 · Cited by 119 · see citing works
Miao, Y., Xie, L., Song, J., Cai, X., Yang, J., Ma, X., Chen, S., & Xie, P. (2024) · Physiological Reports · doi:10.14814/phy2.15917 · Cited by 50 · see citing works
“Additionally, an animal study also found that mitochondrial swelling, mitochondrial cristae remodeling, and membrane rupture in motor neuron terminals were followed by functional failure of the NMJs in aging rats (García et al., 2013).”
BackgroundModeling motor neuron disease: the matter of time
Arbab, M., Baars, S., & Geijsen, N. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2014.07.008 · Cited by 33 · see citing works
- Authors
- García, M. L., Fernández, A., & Solas, M. T.
- Affiliations
- Universidad Complutense de Madrid (ES)
- ORCID
- Fernández, A.
- Venue
- Journal of the Neurological Sciences
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 330
- Issue
- 1-2
- Pages
- 18-26
- ISSN
- 0022-510X (ISSN-L)
- OpenAlex
- W2004311868
- Cited by
- 54
- References
- 52
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 7 · 2023: 3 · 2022: 4 · 2021: 7 · 2020: 4 · 2019: 6 · 2018: 4 · 2017: 3 · 2016: 4 · 2015: 1 · 2014: 8
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the Neurological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- mitochondrial ultrastructure, neuromuscular junction degeneration, mitochondrial swelling, mitochondrial fusion, megamitochondria, calcium overload, cytochrome c, caspase-3, apoptosis, dynein, retrograde transport, dying back, alpha motoneurons, amyotrophic lateral sclerosis, neurodegeneration
- MeSH terms
- Aging, Animals, Axons, Dyneins, Immunohistochemistry, Male, Mitochondria, Mitochondrial Swelling, Motor Neurons, Neuromuscular Junction, Spinal Cord, Tissue Embedding, Tissue Fixation, Rats, Wistar, Apoptosis, Presynaptic Terminals, Cytochromes c, Microscopy, Electron, Transmission, Rats, Caspase 3
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
