Caspase cleavage of several intermediate filament (IF) proteins generates proteolytic fragments that characterize apoptosis as shown for lamins and vimentin. These fragments affect IF assembly in a way that promotes filament aggregation. The hypothesis is that disease-causing mutations in IF proteins and subsequent characteristic histopathological aggregates could involve caspase cleavage of IF proteins. Desmin is a type III IF protein that is expressed mainly in the muscle cells. Heterozygous missense mutations in the desmin gene cause desmin-related myopathy (DRM), a progressive muscle wasting disease. The pathological hallmark of DRM is cytoplasmic desmin-containing aggregates in skeletal and cardiac muscles. The expression of mutant desmin induced filament aggregation and mitochondrial clumping. Accompanied with these changes were caspase activation and desmin proteolysis. In this study, I have demonstrated that desmin is cleaved specifically by caspase-6 at VEMD263 and produces two major cleavage products. While the C-terminal desmin (C-desmin) is unable to assemble into filaments, the N-terminal desmin (N-desmin) forms aggregates and interfere with normal IF assembly. When transiently expressed into a range of cultured cell lines, N-desmin formed cytoplasmic aggregates that also disrupted the endogenous IF networks of desmin, consistent with its effect in vitro. In addition, I have generated a neo-epitope antibody that recognized caspase-cleaved but not the intact desmin. This antibody revealed the presence of the N-desmin in a subset of transfected cells expressing myopathic desmin mutants. Furthermore, expression of mutants induces a cellular stress response and alters mitochondrial morphology. Taken together, these data suggest that the integrity of IF is a key sensor for cell homeostasis and their functional interaction with mitochondria and cell death signaling pathway are central to the progressive muscle degeneration seen in human desminopathies.

Allsopp, T. E., McLuckie, J., Kerr, L. E., Macleod, M., Sharkey, J., & Kelly, J. S. (2000). Caspase 6 activity initiates caspase 3 activation in cerebellar granule cell apoptosis. Cell Death Differ, 7(10), 984-993. doi: 10.1038/sj.cdd.4400733
Almahbobi, G., Williams, L. J., & Hall, P. F. (1992). Attachment of mitochondria to intermediate filaments in adrenal cells: relevance to the regulation of steroid synthesis. Exp Cell Res, 200(2), 361-369.
Alnemri, E. S., Livingston, D. J., Nicholson, D. W., Salvesen, G., Thornberry, N. A., Wong, W. W., & Yuan, J. (1996). Human ICE/CED-3 Protease Nomenclature. Cell, 87(2), 171. doi: http://dx.doi.org/10.1016/S0092-8674(00)81334-3
Ariza, A., Coll, J., Fernandez-Figueras, M. T., Lopez, M. D., Mate, J. L., Garcia, O., . . . Navas-Palacios, J. J. (1995). Desmin myopathy: a multisystem disorder involving skeletal, cardiac, and smooth muscle. Hum Pathol, 26(9), 1032-1037.
Bar, H., Goudeau, B., Walde, S., Casteras-Simon, M., Mucke, N., Shatunov, A., . . . Herrmann, H. (2007). Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies. Hum Mutat, 28(4), 374-386. doi: 10.1002/humu.20459
Bar, H., Kostareva, A., Sjoberg, G., Sejersen, T., Katus, H. A., & Herrmann, H. (2006). Forced expression of desmin and desmin mutants in cultured cells: impact of myopathic missense mutations in the central coiled-coil domain on network formation. Exp Cell Res, 312(9), 1554-1565. doi: 10.1016/j.yexcr.2006.01.021
Bar, H., Mucke, N., Kostareva, A., Sjoberg, G., Aebi, U., & Herrmann, H. (2005). Severe muscle disease-causing desmin mutations interfere with in vitro filament assembly at distinct stages. Proc Natl Acad Sci U S A, 102(42), 15099-15104. doi: 10.1073/pnas.0504568102
Bar, H., Sharma, S., Kleiner, H., Mucke, N., Zentgraf, H., Katus, H. A., . . . Herrmann, H. (2009). Interference of amino-terminal desmin fragments with desmin filament formation. Cell Motil Cytoskeleton, 66(11), 986-999. doi: 10.1002/cm.20396
Basha, E., O'Neill, H., & Vierling, E. (2012). Small heat shock proteins and alpha-crystallins: dynamic proteins with flexible functions. Trends Biochem Sci, 37(3), 106-117. doi: 10.1016/j.tibs.2011.11.005
Benard, G., Bellance, N., James, D., Parrone, P., Fernandez, H., Letellier, T., & Rossignol, R. (2007). Mitochondrial bioenergetics and structural network organization. J Cell Sci, 120(Pt 5), 838-848. doi: 10.1242/jcs.03381
Bereiter-Hahn, J., & Voth, M. (1994). Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech, 27(3), 198-219. doi: 10.1002/jemt.1070270303
Boatright, K. M., & Salvesen, G. S. (2003). Mechanisms of caspase activation. Curr Opin Cell Biol, 15(6), 725-731.
Boriek, A. M., Capetanaki, Y., Hwang, W., Officer, T., Badshah, M., Rodarte, J., & Tidball, J. G. (2001). Desmin integrates the three-dimensional mechanical properties of muscles. Am J Physiol Cell Physiol, 280(1), C46-52.
Bova, M. P., Yaron, O., Huang, Q., Ding, L., Haley, D. A., Stewart, P. L., & Horwitz, J. (1999). Mutation R120G in αB-crystallin, which is linked to a desmin-related myopathy, results in an irregular structure and defective chaperone-like function. Proceedings of the National Academy of Sciences, 96(11), 6137-6142. doi: 10.1073/pnas.96.11.6137
Brakenhoff, R. H., Guerts van Kessel, A. H., Oldenburg, M., Wijnen, J. T., Bloemendal, H., Meera Khan, P., & Schoenmakers, J. G. (1990). Human alpha B-crystallin (CRYA2) gene mapped to chromosome 11q12-q23. Hum Genet, 85(2), 237-240.
Breckenridge, D. G., Stojanovic, M., Marcellus, R. C., & Shore, G. C. (2003). Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J Cell Biol, 160(7), 1115-1127. doi: 10.1083/jcb.200212059
Brownlees, J., Ackerley, S., Grierson, A. J., Jacobsen, N. J., Shea, K., Anderton, B. H., . . . Miller, C. C. (2002). Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport. Hum Mol Genet, 11(23), 2837-2844.
Byun, Y., Chen, F., Chang, R., Trivedi, M., Green, K. J., & Cryns, V. L. (2001). Caspase cleavage of vimentin disrupts intermediate filaments and promotes apoptosis. Cell Death Differ, 8(5), 443-450. doi: 10.1038/sj.cdd.4400840
Cairns, N. J., Lee, V. M., & Trojanowski, J. Q. (2004). The cytoskeleton in neurodegenerative diseases. J Pathol, 204(4), 438-449. doi: 10.1002/path.1650
Capetanaki, Y. (2002). Desmin cytoskeleton: a potential regulator of muscle mitochondrial behavior and function. Trends Cardiovasc Med, 12(8), 339-348.
Capetanaki, Y., Bloch, R. J., Kouloumenta, A., Mavroidis, M., & Psarras, S. (2007). Muscle intermediate filaments and their links to membranes and membranous organelles. Exp Cell Res, 313(10), 2063-2076. doi: 10.1016/j.yexcr.2007.03.033
Capetanaki, Y., Milner, D. J., & Weitzer, G. (1997). Desmin in muscle formation and maintenance: knockouts and consequences. Cell Struct Funct, 22(1), 103-116.
Carmo-Fonseca, M., & David-Ferreira, J. F. (1990). Interactions of intermediate filaments with cell structures. Electron Microscopy Reviews, 3(1), 115-141. doi: 10.1016/0892-0354(90)90017-M
Caulin, C., Salvesen, G. S., & Oshima, R. G. (1997). Caspase cleavage of keratin 18 and reorganization of intermediate filaments during epithelial cell apoptosis. J Cell Biol, 138(6), 1379-1394.
Chan, D. C. (2006). Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol, 22, 79-99. doi: 10.1146/annurev.cellbio.22.010305.104638
Chavez Zobel, A. T., Loranger, A., Marceau, N., Theriault, J. R., Lambert, H., & Landry, J. (2003). Distinct chaperone mechanisms can delay the formation of aggresomes by the myopathy-causing R120G alphaB-crystallin mutant. Hum Mol Genet, 12(13), 1609-1620.
Chen, F., Chang, R., Trivedi, M., Capetanaki, Y., & Cryns, V. L. (2003). Caspase proteolysis of desmin produces a dominant-negative inhibitor of intermediate filaments and promotes apoptosis. J Biol Chem, 278(9), 6848-6853. doi: 10.1074/jbc.M212021200
Chen, H., Chomyn, A., & Chan, D. C. (2005). Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem, 280(28), 26185-26192. doi: 10.1074/jbc.M503062200
Chen, H., Detmer, S. A., Ewald, A. J., Griffin, E. E., Fraser, S. E., & Chan, D. C. (2003). Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol, 160(2), 189-200. doi: 10.1083/jcb.200211046
Chen, M. H., Hagemann, T. L., Quinlan, R. A., Messing, A., & Perng, M. D. (2013). Caspase cleavage of GFAP produces an assembly-compromised proteolytic fragment that promotes filament aggregation. ASN Neuro, 5(5), e00125. doi: 10.1042/an20130032
Chen, Q., Liu, J. B., Horak, K. M., Zheng, H., Kumarapeli, A. R., Li, J., . . . Wang, X. (2005). Intrasarcoplasmic amyloidosis impairs proteolytic function of proteasomes in cardiomyocytes by compromising substrate uptake. Circ Res, 97(10), 1018-1026. doi: 10.1161/01.RES.0000189262.92896.0b
Cipolat, S., Martins de Brito, O., Dal Zilio, B., & Scorrano, L. (2004). OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A, 101(45), 15927-15932. doi: 10.1073/pnas.0407043101
Clark, K. A., McElhinny, A. S., Beckerle, M. C., & Gregorio, C. C. (2002). Striated muscle cytoarchitecture: an intricate web of form and function. Annu Rev Cell Dev Biol, 18, 637-706. doi: 10.1146/annurev.cellbio.18.012502.105840
Clemen, C. S., Herrmann, H., Strelkov, S. V., & Schroder, R. (2013). Desminopathies: pathology and mechanisms. Acta Neuropathol, 125(1), 47-75. doi: 10.1007/s00401-012-1057-6
Cowling, V., & Downward, J. (2002). Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway: absolute requirement for removal of caspase-6 prodomain. Cell Death Differ, 9(10), 1046-1056. doi: 10.1038/sj.cdd.4401065
Dagvadorj, A., Goudeau, B., Hilton-Jones, D., Blancato, J. K., Shatunov, A., Simon-Casteras, M., . . . Vicart, P. (2003). Respiratory insufficiency in desminopathy patients caused by introduction of proline residues in desmin c-terminal alpha-helical segment. Muscle Nerve, 27(6), 669-675. doi: 10.1002/mus.10370
Dagvadorj, A., Olive, M., Urtizberea, J. A., Halle, M., Shatunov, A., Bonnemann, C., . . . Goldfarb, L. G. (2004). A series of West European patients with severe cardiac and skeletal myopathy associated with a de novo R406W mutation in desmin. J Neurol, 251(2), 143-149. doi: 10.1007/s00415-004-0289-3
Dalakas, M. C., Park, K. Y., Semino-Mora, C., Lee, H. S., Sivakumar, K., & Goldfarb, L. G. (2000). Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. N Engl J Med, 342(11), 770-780. doi: 10.1056/nejm200003163421104
David-Ferreira, K. L., & David-Ferreira, J. F. (1980). Association between intermediate-sized filaments and mitochondria in rat Leydig cells. Cell Biol Int Rep, 4(7), 655-662.
Der Perng, M., Su, M., Wen, S. F., Li, R., Gibbon, T., Prescott, A. R., . . . Quinlan, R. A. (2006). The Alexander disease-causing glial fibrillary acidic protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of alpha B-crystallin and HSP27. Am J Hum Genet, 79(2), 197-213. doi: 10.1086/504411
Desagher, S., & Martinou, J. C. (2000). Mitochondria as the central control point of apoptosis. Trends Cell Biol, 10(9), 369-377.
Dubin, R. A., Ally, A. H., Chung, S., & Piatigorsky, J. (1990). Human alpha B-crystallin gene and preferential promoter function in lens. Genomics, 7(4), 594-601.
Escobar-Khondiker, M., Hollerhage, M., Muriel, M. P., Champy, P., Bach, A., Depienne, C., . . . Hoglinger, G. U. (2007). Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. J Neurosci, 27(29), 7827-7837. doi: 10.1523/jneurosci.1644-07.2007
Fardeau, M., Godet-Guillain, J., Tome, F. M., Collin, H., Gaudeau, S., Boffety, C., & Vernant, P. (1978). [A new familial muscular disorder demonstrated by the intra-sarcoplasmic accumulation of a granulo-filamentous material which is dense on electron microscopy (author's transl)]. Rev Neurol (Paris), 134(6-7), 411-425.
Feichtinger, R. G., Sperl, W., Bauer, J. W., & Kofler, B. (2014). Mitochondrial dysfunction: a neglected component of skin diseases. Exp Dermatol. doi: 10.1111/exd.12484
Frank, S., Gaume, B., Bergmann-Leitner, E. S., Leitner, W. W., Robert, E. G., Catez, F., . . . Youle, R. J. (2001). The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell, 1(4), 515-525.
Fuchs, E., & Weber, K. (1994). Intermediate filaments: structure, dynamics, function, and disease. Annu Rev Biochem, 63, 345-382. doi: 10.1146/annurev.bi.63.070194.002021
Furst, D. O., Osborn, M., & Weber, K. (1989). Myogenesis in the mouse embryo: differential onset of expression of myogenic proteins and the involvement of titin in myofibril assembly. J Cell Biol, 109(2), 517-527.
Galluzzi, L., Kepp, O., & Kroemer, G. (2012). Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol, 13(12), 780-788. doi: 10.1038/nrm3479
Gard, D. L., & Lazarides, E. (1980). The synthesis and distribution of desmin and vimentin during myogenesis in vitro. Cell, 19(1), 263-275.
Georgatos, S. D., Weber, K., Geisler, N., & Blobel, G. (1987). Binding of two desmin derivatives to the plasma membrane and the nuclear envelope of avian erythrocytes: evidence for a conserved site-specificity in intermediate filament-membrane interactions. Proc Natl Acad Sci U S A, 84(19), 6780-6784.
Gilbert, S., Loranger, A., Daigle, N., & Marceau, N. (2001). Simple epithelium keratins 8 and 18 provide resistance to Fas-mediated apoptosis. The protection occurs through a receptor-targeting modulation. J Cell Biol, 154(4), 763-773. doi: 10.1083/jcb.200102130
Goebel, H. H. (1995). Desmin-related neuromuscular disorders. Muscle Nerve, 18(11), 1306-1320. doi: 10.1002/mus.880181114
Goebel, H. H., Voit, T., Warlo, I., Jacobs, K., Johannsen, U., & Muller, C. R. (1994). Immunohistologic and electron microscopic abnormalities of desmin and dystrophin in familial cardiomyopathy and myopathy. Rev Neurol (Paris), 150(6-7), 452-459.
Goldfarb, L. G., & Dalakas, M. C. (2009). Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease. J Clin Invest, 119(7), 1806-1813. doi: 10.1172/JCI38027
Goldfarb, L. G., Park, K. Y., Cervenakova, L., Gorokhova, S., Lee, H. S., Vasconcelos, O., . . . Dalakas, M. C. (1998). Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nat Genet, 19(4), 402-403. doi: 10.1038/1300
Golenhofen, N., Htun, P., Ness, W., Koob, R., Schaper, W., & Drenckhahn, D. (1999). Binding of the stress protein alpha B-crystallin to cardiac myofibrils correlates with the degree of myocardial damage during ischemia/reperfusion in vivo. J Mol Cell Cardiol, 31(3), 569-580. doi: 10.1006/jmcc.1998.0892
Goudeau, B., Rodrigues-Lima, F., Fischer, D., Casteras-Simon, M., Sambuughin, N., de Visser, M., . . . Vicart, P. (2006). Variable pathogenic potentials of mutations located in the desmin alpha-helical domain. Hum Mutat, 27(9), 906-913. doi: 10.1002/humu.20351
Griparic, L., van der Wel, N. N., Orozco, I. J., Peters, P. J., & van der Bliek, A. M. (2004). Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. J Biol Chem, 279(18), 18792-18798. doi: 10.1074/jbc.M400920200
Herrmann, H., & Aebi, U. (2004). Intermediate filaments: molecular structure, assembly mechanism, and integration into functionally distinct intracellular Scaffolds. Annu Rev Biochem, 73, 749-789. doi: 10.1146/annurev.biochem.73.011303.073823
Herrmann, H., Bar, H., Kreplak, L., Strelkov, S. V., & Aebi, U. (2007). Intermediate filaments: from cell architecture to nanomechanics. Nat Rev Mol Cell Biol, 8(7), 562-573. doi: 10.1038/nrm2197
Herrmann, H., Haner, M., Brettel, M., Ku, N. O., & Aebi, U. (1999). Characterization of distinct early assembly units of different intermediate filament proteins. J Mol Biol, 286(5), 1403-1420. doi: 10.1006/jmbi.1999.2528
Hesse, M., Magin, T. M., & Weber, K. (2001). Genes for intermediate filament proteins and the draft sequence of the human genome: novel keratin genes and a surprisingly high number of pseudogenes related to keratin genes 8 and 18. J Cell Sci, 114(Pt 14), 2569-2575.
Hirata, H., Takahashi, A., Kobayashi, S., Yonehara, S., Sawai, H., Okazaki, T., . . . Sasada, M. (1998). Caspases are activated in a branched protease cascade and control distinct downstream processes in Fas-induced apoptosis. J Exp Med, 187(4), 587-600.
Hoppins, S., Lackner, L., & Nunnari, J. (2007). The machines that divide and fuse mitochondria. Annu Rev Biochem, 76, 751-780. doi: 10.1146/annurev.biochem.76.071905.090048
Horwitz, J. (2000). The function of alpha-crystallin in vision. Semin Cell Dev Biol, 11(1), 53-60. doi: 10.1006/scdb.1999.0351
Jakobs, S., Martini, N., Schauss, A. C., Egner, A., Westermann, B., & Hell, S. W. (2003). Spatial and temporal dynamics of budding yeast mitochondria lacking the division component Fis1p. J Cell Sci, 116(Pt 10), 2005-2014. doi: 10.1242/jcs.00423
Jessup, M., Abraham, W. T., Casey, D. E., Feldman, A. M., Francis, G. S., Ganiats, T. G., . . . Yancy, C. W. (2009). 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in AdultsA Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. Journal of the American College of Cardiology, 53(15), 1343-1382. doi: 10.1016/j.jacc.2008.11.009
Kam, P. C., & Ferch, N. I. (2000). Apoptosis: mechanisms and clinical implications. Anaesthesia, 55(11), 1081-1093.
Karbowski, M., Spodnik, J. H., Teranishi, M., Wozniak, M., Nishizawa, Y., Usukura, J., & Wakabayashi, T. (2001). Opposite effects of microtubule-stabilizing and microtubule-destabilizing drugs on biogenesis of mitochondria in mammalian cells. J Cell Sci, 114(Pt 2), 281-291.
Kay, L., Li, Z., Mericskay, M., Olivares, J., Tranqui, L., Fontaine, E., . . . Saks, V. A. (1997). Study of regulation of mitochondrial respiration in vivo. An analysis of influence of ADP diffusion and possible role of cytoskeleton. Biochim Biophys Acta, 1322(1), 41-59.
Kostareva, A., Sjoberg, G., Bruton, J., Zhang, S. J., Balogh, J., Gudkova, A., . . . Sejersen, T. (2008). Mice expressing L345P mutant desmin exhibit morphological and functional changes of skeletal and cardiac mitochondria. J Muscle Res Cell Motil, 29(1), 25-36. doi: 10.1007/s10974-008-9139-8
Kotiadis, V. N., Duchen, M. R., & Osellame, L. D. (2014). Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health. Biochim Biophys Acta, 1840(4), 1254-1265. doi: 10.1016/j.bbagen.2013.10.041
Ku, N. O., Liao, J., & Omary, M. B. (1997). Apoptosis generates stable fragments of human type I keratins. J Biol Chem, 272(52), 33197-33203.
Ku, N. O., & Omary, M. B. (2001). Effect of mutation and phosphorylation of type I keratins on their caspase-mediated degradation. J Biol Chem, 276(29), 26792-26798. doi: 10.1074/jbc.M103315200
Kubli, D. A., & Gustafsson, A. B. (2012). Mitochondria and mitophagy: the yin and yang of cell death control. Circ Res, 111(9), 1208-1221. doi: 10.1161/circresaha.112.265819
Kuznetsov, A. V., Javadov, S., Guzun, R., Grimm, M., & Saks, V. (2013). Cytoskeleton and regulation of mitochondrial function: the role of beta-tubulin II. Front Physiol, 4, 82. doi: 10.3389/fphys.2013.00082
Lee, Y. J., Jeong, S. Y., Karbowski, M., Smith, C. L., & Youle, R. J. (2004). Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell, 15(11), 5001-5011. doi: 10.1091/mbc.E04-04-0294
Legros, F., Lombes, A., Frachon, P., & Rojo, M. (2002). Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins. Mol Biol Cell, 13(12), 4343-4354. doi: 10.1091/mbc.E02-06-0330
Leterrier, J. F., Rusakov, D. A., Nelson, B. D., & Linden, M. (1994). Interactions between brain mitochondria and cytoskeleton: evidence for specialized outer membrane domains involved in the association of cytoskeleton-associated proteins to mitochondria in situ and in vitro. Microsc Res Tech, 27(3), 233-261.
Li, M., & Dalakas, M. C. (2001). Abnormal desmin protein in myofibrillar myopathies caused by desmin gene mutations. Ann Neurol, 49(4), 532-536.
Li, Z., Colucci-Guyon, E., Pincon-Raymond, M., Mericskay, M., Pournin, S., Paulin, D., & Babinet, C. (1996). Cardiovascular lesions and skeletal myopathy in mice lacking desmin. Dev Biol, 175(2), 362-366. doi: 10.1006/dbio.1996.0122
Li, Z. L., Lilienbaum, A., Butler-Browne, G., & Paulin, D. (1989). Human desmin-coding gene: complete nucleotide sequence, characterization and regulation of expression during myogenesis and development. Gene, 78(2), 243-254.
Lin, A., Krockmalnic, G., & Penman, S. (1990). Imaging cytoskeleton--mitochondrial membrane attachments by embedment-free electron microscopy of saponin-extracted cells. Proc Natl Acad Sci U S A, 87(21), 8565-8569.
Linden, M., Li, Z., Paulin, D., Gotow, T., & Leterrier, J. F. (2001). Effects of desmin gene knockout on mice heart mitochondria. J Bioenerg Biomembr, 33(4), 333-341.
Liu, J., Chen, Q., Huang, W., Horak, K. M., Zheng, H., Mestril, R., & Wang, X. (2006). Impairment of the ubiquitin-proteasome system in desminopathy mouse hearts. Faseb j, 20(2), 362-364. doi: 10.1096/fj.05-4869fje
Liu, J., Tang, M., Mestril, R., & Wang, X. (2006). Aberrant protein aggregation is essential for a mutant desmin to impair the proteolytic function of the ubiquitin-proteasome system in cardiomyocytes. J Mol Cell Cardiol, 40(4), 451-454. doi: 10.1016/j.yjmcc.2005.12.011
Liu, X., Weaver, D., Shirihai, O., & Hajnoczky, G. (2009). Mitochondrial 'kiss-and-run': interplay between mitochondrial motility and fusion-fission dynamics. Embo j, 28(20), 3074-3089. doi: 10.1038/emboj.2009.255
Los, M., Wesselborg, S., & Schulze-Osthoff, K. (1999). The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice. Immunity, 10(6), 629-639.
Lunemann, J. D., Schmidt, J., Schmid, D., Barthel, K., Wrede, A., Dalakas, M. C., & Munz, C. (2007). Beta-amyloid is a substrate of autophagy in sporadic inclusion body myositis. Ann Neurol, 61(5), 476-483. doi: 10.1002/ana.21115
MacArthur, M. W., & Thornton, J. M. (1991). Influence of proline residues on protein conformation. J Mol Biol, 218(2), 397-412.
Maloyan, A., Sanbe, A., Osinska, H., Westfall, M., Robinson, D., Imahashi, K., . . . Robbins, J. (2005). Mitochondrial dysfunction and apoptosis underlie the pathogenic process in alpha-B-crystallin desmin-related cardiomyopathy. Circulation, 112(22), 3451-3461. doi: 10.1161/CIRCULATIONAHA.105.572552
Marceau, N., Schutte, B., Gilbert, S., Loranger, A., Henfling, M. E., Broers, J. L., . . . Ramaekers, F. C. (2007). Dual roles of intermediate filaments in apoptosis. Exp Cell Res, 313(10), 2265-2281. doi: 10.1016/j.yexcr.2007.03.038
Martin, J. L., Mestril, R., Hilal-Dandan, R., Brunton, L. L., & Dillmann, W. H. (1997). Small heat shock proteins and protection against ischemic injury in cardiac myocytes. Circulation, 96(12), 4343-4348.
Mattenberger, Y., James, D. I., & Martinou, J. C. (2003). Fusion of mitochondria in mammalian cells is dependent on the mitochondrial inner membrane potential and independent of microtubules or actin. FEBS Lett, 538(1-3), 53-59.
McLendon, P. M., & Robbins, J. (2011). Desmin-related cardiomyopathy: an unfolding story. Am J Physiol Heart Circ Physiol, 301(4), H1220-1228. doi: 10.1152/ajpheart.00601.2011
Milner, D. J., Mavroidis, M., Weisleder, N., & Capetanaki, Y. (2000). Desmin cytoskeleton linked to muscle mitochondrial distribution and respiratory function. J Cell Biol, 150(6), 1283-1298.
Milner, D. J., Weitzer, G., Tran, D., Bradley, A., & Capetanaki, Y. (1996). Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. J Cell Biol, 134(5), 1255-1270.
Morishima, N. (1999). Changes in nuclear morphology during apoptosis correlate with vimentin cleavage by different caspases located either upstream or downstream of Bcl-2 action. Genes Cells, 4(7), 401-414.
Mose-Larsen, P., Bravo, R., Fey, S. J., Small, J. V., & Celis, J. E. (1982). Putative association of mitochondria with a subpopulation of intermediate-sized filaments in cultured human skin fibroblasts. Cell, 31(3 Pt 2), 681-692.
Munoz-Marmol, A. M., Strasser, G., Isamat, M., Coulombe, P. A., Yang, Y., Roca, X., . . . Fuchs, E. (1998). A dysfunctional desmin mutation in a patient with severe generalized myopathy. Proc Natl Acad Sci U S A, 95(19), 11312-11317.
Nakanishi, K., Maruyama, M., Shibata, T., & Morishima, N. (2001). Identification of a caspase-9 substrate and detection of its cleavage in programmed cell death during mouse development. J Biol Chem, 276(44), 41237-41244. doi: 10.1074/jbc.M105648200
Nekrasova, O. E., Mendez, M. G., Chernoivanenko, I. S., Tyurin-Kuzmin, P. A., Kuczmarski, E. R., Gelfand, V. I., . . . Minin, A. A. (2011). Vimentin intermediate filaments modulate the motility of mitochondria. Mol Biol Cell, 22(13), 2282-2289. doi: 10.1091/mbc.E10-09-0766
Noske, A. B., Costin, A. J., Morgan, G. P., & Marsh, B. J. (2008). Expedited approaches to whole cell electron tomography and organelle mark-up in situ in high-pressure frozen pancreatic islets. J Struct Biol, 161(3), 298-313. doi: 10.1016/j.jsb.2007.09.015
Ono, T., Isobe, K., Nakada, K., & Hayashi, J. I. (2001). Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat Genet, 28(3), 272-275. doi: 10.1038/90116
Orrenius, S., Gogvadze, V., & Zhivotovsky, B. (2007). Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol, 47, 143-183. doi: 10.1146/annurev.pharmtox.47.120505.105122
Orth, K., Chinnaiyan, A. M., Garg, M., Froelich, C. J., & Dixit, V. M. (1996). The CED-3/ICE-like protease Mch2 is activated during apoptosis and cleaves the death substrate lamin A. J Biol Chem, 271(28), 16443-16446.
Oshima, R. G. (2002). Apoptosis and kerat inintermediate filaments. Cell Death Differ, 9(5), 486-592.
Otsu, N. (1979). A Threshold Selection Method from Gray-Level Histograms. Systems, Man and Cybernetics, IEEE Transactions on, 9(1), 62-66. doi: 10.1109/TSMC.1979.4310076
Ott, M., Robertson, J. D., Gogvadze, V., Zhivotovsky, B., & Orrenius, S. (2002). Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci U S A, 99(3), 1259-1263. doi: 10.1073/pnas.241655498
Panagopoulou, P., Davos, C. H., Milner, D. J., Varela, E., Cameron, J., Mann, D. L., & Capetanaki, Y. (2008). Desmin mediates TNF-alpha-induced aggregate formation and intercalated disk reorganization in heart failure. J Cell Biol, 181(5), 761-775. doi: 10.1083/jcb.200710049
Park, K. Y., Dalakas, M. C., Semino-Mora, C., Lee, H. S., Litvak, S., Takeda, K., . . . Goldfarb, L. G. (2000). Sporadic cardiac and skeletal myopathy caused by a de novo desmin mutation. Clin Genet, 57(6), 423-429.
Peng, J. Y., Lin, C. C., Chen, Y. J., Kao, L. S., Liu, Y. C., Chou, C. C., . . . Hsu, C. N. (2011). Automatic morphological subtyping reveals new roles of caspases in mitochondrial dynamics. PLoS Comput Biol, 7(10), e1002212. doi: 10.1371/journal.pcbi.1002212
Peng, J. Y., Lin, C. C., & Hsu, C. N. (2010). Adaptive Local Thresholding for Flourescence Cell Micrographs. In: Proceedings of the 2010 Conferenceon Technologies and Applications of Artificial Intelligence (TAAI2010). Hsinchu,Taiwan : Taiwanese Association for AI., pp9-16.
Perez-Olle, R., Lopez-Toledano, M. A., Goryunov, D., Cabrera-Poch, N., Stefanis, L., Brown, K., & Liem, R. K. (2005). Mutations in the neurofilament light gene linked to Charcot-Marie-Tooth disease cause defects in transport. J Neurochem, 93(4), 861-874. doi: 10.1111/j.1471-4159.2005.03095.x
Perkins, G., Bossy-Wetzel, E., & Ellisman, M. H. (2009). New insights into mitochondrial structure during cell death. Exp Neurol, 218(2), 183-192. doi: 10.1016/j.expneurol.2009.05.021
Pinol-Ripoll, G., Shatunov, A., Cabello, A., Larrode, P., de la Puerta, I., Pelegrin, J., . . . Goldfarb, L. G. (2009). Severe infantile-onset cardiomyopathy associated with a homozygous deletion in desmin. Neuromuscul Disord, 19(6), 418-422. doi: 10.1016/j.nmd.2009.04.004
Poon, E., Howman, E. V., Newey, S. E., & Davies, K. E. (2002). Association of syncoilin and desmin: linking intermediate filament proteins to the dystrophin-associated protein complex. J Biol Chem, 277(5), 3433-3439. doi: 10.1074/jbc.M105273200
Price, M. G. (1984). Molecular analysis of intermediate filament cytoskeleton--a putative load-bearing structure. Am J Physiol, 246(4 Pt 2), H566-572.
Rao, L., Perez, D., & White, E. (1996). Lamin proteolysis facilitates nuclear events during apoptosis. J Cell Biol, 135(6 Pt 1), 1441-1455.
Reers, M., Smith, T. W., & Chen, L. B. (1991). J-aggregate formation of a carbocyanine as a quantitative fluorescent indicator of membrane potential. Biochemistry, 30(18), 4480-4486.
Reipert, S., Steinbock, F., Fischer, I., Bittner, R. E., Zeold, A., & Wiche, G. (1999). Association of mitochondria with plectin and desmin intermediate filaments in striated muscle. Exp Cell Res, 252(2), 479-491. doi: 10.1006/excr.1999.4626
Rezniczek, G. A., Abrahamsberg, C., Fuchs, P., Spazierer, D., & Wiche, G. (2003). Plectin 5'-transcript diversity: short alternative sequences determine stability of gene products, initiation of translation and subcellular localization of isoforms. Hum Mol Genet, 12(23), 3181-3194. doi: 10.1093/hmg/ddg345
Rojo, M., Legros, F., Chateau, D., & Lombes, A. (2002). Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci, 115(Pt 8), 1663-1674.
Ruchaud, S., Korfali, N., Villa, P., Kottke, T. J., Dingwall, C., Kaufmann, S. H., & Earnshaw, W. C. (2002). Caspase-6 gene disruption reveals a requirement for lamin A cleavage in apoptotic chromatin condensation. Embo j, 21(8), 1967-1977. doi: 10.1093/emboj/21.8.1967
Ryan, M. T., Muller, H., & Pfanner, N. (1999). Functional staging of ADP/ATP carrier translocation across the outer mitochondrial membrane. J Biol Chem, 274(29), 20619-20627.
Sahlgren, C. M., Pallari, H. M., He, T., Chou, Y. H., Goldman, R. D., & Eriksson, J. E. (2006). A nestin scaffold links Cdk5/p35 signaling to oxidant-induced cell death. Embo j, 25(20), 4808-4819. doi: 10.1038/sj.emboj.7601366
Sanbe, A., Osinska, H., Saffitz, J. E., Glabe, C. G., Kayed, R., Maloyan, A., & Robbins, J. (2004). Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis. Proc Natl Acad Sci U S A, 101(27), 10132-10136. doi: 10.1073/pnas.0401900101
Sanbe, A., Osinska, H., Villa, C., Gulick, J., Klevitsky, R., Glabe, C. G., . . . Robbins, J. (2005). Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy. Proc Natl Acad Sci U S A, 102(38), 13592-13597. doi: 10.1073/pnas.0503324102
Schroder, R., Goudeau, B., Simon, M. C., Fischer, D., Eggermann, T., Clemen, C. S., . . . Vicart, P. (2003). On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria. Hum Mol Genet, 12(6), 657-669. doi: 10.1093/hmg/ddg060
Schroder, R., Warlo, I., Herrmann, H., van der Ven, P. F., Klasen, C., Blumcke, I., . . . Magin, T. M. (1999). Immunogold EM reveals a close association of plectin and the desmin cytoskeleton in human skeletal muscle. Eur J Cell Biol, 78(4), 288-295. doi: 10.1016/s0171-9335(99)80062-4
Schultheiss, T., Lin, Z. X., Ishikawa, H., Zamir, I., Stoeckert, C. J., & Holtzer, H. (1991). Desmin/vimentin intermediate filaments are dispensable for many aspects of myogenesis. J Cell Biol, 114(5), 953-966.
Schweitzer, S. C., Klymkowsky, M. W., Bellin, R. M., Robson, R. M., Capetanaki, Y., & Evans, R. M. (2001). Paranemin and the organization of desmin filament networks. J Cell Sci, 114(Pt 6), 1079-1089.
Selcen, D., Muntoni, F., Burton, B. K., Pegoraro, E., Sewry, C., Bite, A. V., & Engel, A. G. (2009). Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Ann Neurol, 65(1), 83-89. doi: 10.1002/ana.21553
Sinha, K., Das, J., Pal, P. B., & Sil, P. C. (2013). Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol, 87(7), 1157-1180. doi: 10.1007/s00204-013-1034-4
Slee, E. A., Adrain, C., & Martin, S. J. (1999). Serial killers: ordering caspase activation events in apoptosis. Cell Death Differ, 6(11), 1067-1074. doi: 10.1038/sj.cdd.4400601
Smiley, S. T., Reers, M., Mottola-Hartshorn, C., Lin, M., Chen, A., Smith, T. W., . . . Chen, L. B. (1991). Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. Proc Natl Acad Sci U S A, 88(9), 3671-3675.
Song, Z., Chen, H., Fiket, M., Alexander, C., & Chan, D. C. (2007). OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol, 178(5), 749-755. doi: 10.1083/jcb.200704110
Suen, D. F., Norris, K. L., & Youle, R. J. (2008). Mitochondrial dynamics and apoptosis. Genes Dev, 22(12), 1577-1590. doi: 10.1101/gad.1658508
Sugawara, M., Kato, K., Komatsu, M., Wada, C., Kawamura, K., Shindo, P. S., . . . Toyoshima, I. (2000). A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates. Neurology, 55(7), 986-990.
Tait, S. W., & Green, D. R. (2012). Mitochondria and cell signalling. J Cell Sci, 125(Pt 4), 807-815. doi: 10.1242/jcs.099234
Takahashi, A., Alnemri, E. S., Lazebnik, Y. A., Fernandes-Alnemri, T., Litwack, G., Moir, R. D., . . . Earnshaw, W. C. (1996). Cleavage of lamin A by Mch2 alpha but not CPP32: multiple interleukin 1 beta-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis. Proc Natl Acad Sci U S A, 93(16), 8395-8400.
Talanian, R. V., Quinlan, C., Trautz, S., Hackett, M. C., Mankovich, J. A., Banach, D., . . . Wong, W. W. (1997). Substrate specificities of caspase family proteases. J Biol Chem, 272(15), 9677-9682.
Tanaka, Y., Kanai, Y., Okada, Y., Nonaka, S., Takeda, S., Harada, A., & Hirokawa, N. (1998). Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell, 93(7), 1147-1158.
Tannous, P., Zhu, H., Johnstone, J. L., Shelton, J. M., Rajasekaran, N. S., Benjamin, I. J., . . . Hill, J. A. (2008). Autophagy is an adaptive response in desmin-related cardiomyopathy. Proceedings of the National Academy of Sciences, 105(28), 9745-9750. doi: 10.1073/pnas.0706802105
Tao, G. Z., Looi, K. S., Toivola, D. M., Strnad, P., Zhou, Q., Liao, J., . . . Omary, M. B. (2009). Keratins modulate the shape and function of hepatocyte mitochondria: a mechanism for protection from apoptosis. J Cell Sci, 122(Pt 21), 3851-3855. doi: 10.1242/jcs.051862
Taylor, M. R., Slavov, D., Ku, L., Di Lenarda, A., Sinagra, G., Carniel, E., . . . Bank, B. D. (2007). Prevalence of desmin mutations in dilated cardiomyopathy. Circulation, 115(10), 1244-1251. doi: 10.1161/CIRCULATIONAHA.106.646778
Thornberry, N. A., Rano, T. A., Peterson, E. P., Rasper, D. M., Timkey, T., Garcia-Calvo, M., . . . Nicholson, D. W. (1997). A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J Biol Chem, 272(29), 17907-17911.
Thornell, L., Carlsson, L., Li, Z., Mericskay, M., & Paulin, D. (1997). Null mutation in the desmin gene gives rise to a cardiomyopathy. J Mol Cell Cardiol, 29(8), 2107-2124.
Toivola, D. M., Tao, G. Z., Habtezion, A., Liao, J., & Omary, M. B. (2005). Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments. Trends Cell Biol, 15(11), 608-617. doi: 10.1016/j.tcb.2005.09.004
Tolstonog, G. V., Belichenko-Weitzmann, I. V., Lu, J. P., Hartig, R., Shoeman, R. L., Traub, U., & Traub, P. (2005). Spontaneously immortalized mouse embryo fibroblasts: growth behavior of wild-type and vimentin-deficient cells in relation to mitochondrial structure and activity. DNA Cell Biol, 24(11), 680-709. doi: 10.1089/dna.2005.24.680
Tolstonog, G. V., Mothes, E., Shoeman, R. L., & Traub, P. (2001). Isolation of SDS-stable complexes of the intermediate filament protein vimentin with repetitive, mobile, nuclear matrix attachment region, and mitochondrial DNA sequence elements from cultured mouse and human fibroblasts. DNA Cell Biol, 20(9), 531-554. doi: 10.1089/104454901317094954
Tolstonog, G. V., Sabasch, M., & Traub, P. (2002). Cytoplasmic intermediate filaments are stably associated with nuclear matrices and potentially modulate their DNA-binding function. DNA Cell Biol, 21(3), 213-239. doi: 10.1089/10445490252925459
Tondera, D., Grandemange, S., Jourdain, A., Karbowski, M., Mattenberger, Y., Herzig, S., . . . Martinou, J. C. (2009). SLP-2 is required for stress-induced mitochondrial hyperfusion. Embo j, 28(11), 1589-1600. doi: 10.1038/emboj.2009.89
Uttam, J., Hutton, E., Coulombe, P. A., Anton-Lamprecht, I., Yu, Q. C., Gedde-Dahl, T., Jr., . . . Fuchs, E. (1996). The genetic basis of epidermolysis bullosa simplex with mottled pigmentation. Proc Natl Acad Sci U S A, 93(17), 9079-9084.
van der Bliek, A. M. (2009). Fussy mitochondria fuse in response to stress. Embo j, 28(11), 1533-1534. doi: 10.1038/emboj.2009.130
van Spaendonck-Zwarts, K. Y., van Hessem, L., Jongbloed, J. D., de Walle, H. E., Capetanaki, Y., van der Kooi, A. J., . . . van Tintelen, J. P. (2011). Desmin-related myopathy. Clin Genet, 80(4), 354-366. doi: 10.1111/j.1399-0004.2010.01512.x
van Tintelen, J. P., Van Gelder, I. C., Asimaki, A., Suurmeijer, A. J., Wiesfeld, A. C., Jongbloed, J. D., . . . van den Berg, M. P. (2009). Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene. Heart Rhythm, 6(11), 1574-1583. doi: 10.1016/j.hrthm.2009.07.041
Vicart, P., Caron, A., Guicheney, P., Li, Z., Prevost, M. C., Faure, A., . . . Fardeau, M. (1998). A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet, 20(1), 92-95. doi: 10.1038/1765
Vicart, P., Dupret, J. M., Hazan, J., Li, Z., Gyapay, G., Krishnamoorthy, R., . . . Paulin, D. (1996). Human desmin gene: cDNA sequence, regional localization and exclusion of the locus in a familial desmin-related myopathy. Hum Genet, 98(4), 422-429.
Viegas-Pequignot, E., Li, Z. L., Dutrillaux, B., Apiou, F., & Paulin, D. (1989). Assignment of human desmin gene to band 2q35 by nonradioactive in situ hybridization. Hum Genet, 83(1), 33-36.
Wagner, O. I., Lifshitz, J., Janmey, P. A., Linden, M., McIntosh, T. K., & Leterrier, J. F. (2003). Mechanisms of mitochondria-neurofilament interactions. J Neurosci, 23(27), 9046-9058.
Wang, X., Osinska, H., Dorn, G. W., 2nd, Nieman, M., Lorenz, J. N., Gerdes, A. M., . . . Robbins, J. (2001). Mouse model of desmin-related cardiomyopathy. Circulation, 103(19), 2402-2407.
Weber, K., & Geisler, N. (1985). Intermediate filaments: structural conservation and divergence. Ann N Y Acad Sci, 455, 126-143.
Weisleder, N., Taffet, G. E., & Capetanaki, Y. (2004). Bcl-2 overexpression corrects mitochondrial defects and ameliorates inherited desmin null cardiomyopathy. Proc Natl Acad Sci U S A, 101(3), 769-774. doi: 10.1073/pnas.0303202101
Wild, P., & Dikic, I. (2010). Mitochondria get a Parkin' ticket. Nat Cell Biol, 12(2), 104-106. doi: 10.1038/ncb0210-104
Winter, L., Abrahamsberg, C., & Wiche, G. (2008). Plectin isoform 1b mediates mitochondrion-intermediate filament network linkage and controls organelle shape. J Cell Biol, 181(6), 903-911. doi: 10.1083/jcb.200710151
Wyllie, A. H. (2010). "Where, O death, is thy sting?" A brief review of apoptosis biology. Mol Neurobiol, 42(1), 4-9. doi: 10.1007/s12035-010-8125-5
Xue, Z. G., Cheraud, Y., Brocheriou, V., Izmiryan, A., Titeux, M., Paulin, D., & Li, Z. (2004). The mouse synemin gene encodes three intermediate filament proteins generated by alternative exon usage and different open reading frames. Exp Cell Res, 298(2), 431-444. doi: 10.1016/j.yexcr.2004.04.023
Yoneda, K., Furukawa, T., Zheng, Y. J., Momoi, T., Izawa, I., Inagaki, M., . . . Inagaki, N. (2004). An autocrine/paracrine loop linking keratin 14 aggregates to tumor necrosis factor alpha-mediated cytotoxicity in a keratinocyte model of epidermolysis bullosa simplex. J Biol Chem, 279(8), 7296-7303. doi: 10.1074/jbc.M307242200
Yoshii, S. R., Kishi, C., Ishihara, N., & Mizushima, N. (2011). Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J Biol Chem, 286(22), 19630-19640. doi: 10.1074/jbc.M110.209338