Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence

Caron, M; Auclair, M; Donadille, B; Béréziat, V; Guerci, B; Laville, M; Narbonne, H; Bodemer, C; Lascols, O; Capeau, J; Vigouroux, C

doi:10.1038/sj.cdd.4402197

Cited by 232Nuclear Structure and FunctionTelomeres, Telomerase, and SenescenceHIV-related health complications and treatments

Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence

Caron, M, Auclair, M, Donadille, B, Béréziat, V, Guerci, B, Laville, M, Narbonne, H, Bodemer, C +3 more·2007·Cell Death & Differentiation

DOI 10.1038/sj.cdd.4402197

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Abstract

Lipodystrophic syndromes associated with mutations in LMNA, encoding A-type lamins, and with HIV antiretroviral treatments share several clinical characteristics. Nuclear alterations and prelamin A accumulation have been reported in fibroblasts from patients with LMNA mutations and adipocytes exposed to protease inhibitors (PI). As genetically altered lamin A maturation also results in premature ageing syndromes with lipodystrophy, we studied prelamin A expression and senescence markers in cultured human fibroblasts bearing six different LMNA mutations or treated with PIs. As compared to control cells, fibroblasts with LMNA mutations or treated with PIs had nuclear shape abnormalities and reduced proliferative activity that worsened with increasing cellular passages. They exhibited prelamin A accumulation, increased oxidative stress, decreased expression of mitochondrial respiratory chain proteins and premature cellular senescence. Inhibition of prelamin A farnesylation prevented cellular senescence and oxidative stress. Adipose tissue samples from patients with LMNA mutations or treated with PIs also showed retention of prelamin A, overexpression of the cell cycle checkpoint inhibitor p16 and altered mitochondrial markers. Thus, both LMNA mutations and PI treatment result in accumulation of farnesylated prelamin A and oxidative stress that trigger premature cellular senescence. These alterations could participate in the pathophysiology of lipodystrophic syndromes and lead to premature ageing complications.

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Protease inhibitors and NRTIs can induce p16 and p21 expression in human adipose tissue.
“To our knowledge, no evidence yet exists on whether antiretroviral compounds can induce senescence in adipocytes in vitro, but it has been demonstrated that protease inhibitors and NRTIs can induce p16 and p21 expression in human adipose tissue (Caron et al, 2007, 2008).”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Caron et al, 2007

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Self-citation
Exploring the pathophysiology behind the more common genetic and acquired lipodystrophies
Nolis, T. (2013) · Journal of Human Genetics · doi:10.1038/jhg.2013.107 · Cited by 87 · see citing works
Adipose tissue biology and HIV-infection
Giralt, M., Domingo, P., & Villarroya, F. (2011) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2010.12.001 · Cited by 85 · see citing works
HGPS and related premature aging disorders: From genomic identification to the first therapeutic approaches
Pereira, S., Bourgeois, P., Navarro, C., Esteves-Vieira, V., Cau, P., De Sandre-Giovannoli, A., & Lévy, N. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.04.003 · Cited by 85 · see citing works
“…and collaborators demonstrated that several LMNA mutations observed in lipodystrophic patients, or in HIV patients treated with some protease inhibitors, resulted in an accumulation of Prelamin A and an increased oxidative stress that triggers premature cellular senescence (Caron et al., 2007).”
HIV-associated cellular senescence: A contributor to accelerated aging
Cohen, J., & Torres, C. A. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.12.004 · Cited by 87 · see citing works
“Adipose tissue from lipodystrophic HIV-infected patients who were on these PIs showed an increase in the senescence marker p16, providing an in vivo relationship between senescence and lipodystrophy (Caron et al., 2007).”
A lipodystrophy-causing lamin A mutant alters conformation and epigenetic regulation of the anti-adipogenic MIR335 locus
Oldenburg, A. R., Briand, N., Sørensen, A. L., Cahyani, I., Shah, A., Moskaug, J. Ø., & Collas, P. (2017) · The Journal of Cell Biology · doi:10.1083/jcb.201701043 · Cited by 85 · see citing works
Lamin A involvement in ageing processes
Cenni, V., Capanni, C., Mattioli, E., Schena, E., Squarzoni, S., Bacalini, M. G., Garagnani, P., Salvioli, S., Franceschi, C., & Lattanzi, G. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101073 · Cited by 85 · see citing works
Premature Senescence of Vascular Cells Is Induced by HIV Protease Inhibitors: Implication of Prelamin A and Reversion by Statin
Lefèvre, C., Auclair, M., Boccara, F., Bastard, J.-P., Capeau, J., Vigouroux, C., & Caron-Debarle, M. (2010) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.110.213603 · Cited by 77 · see citing works
Self-citation
Adipokines and Aging
Arai, Y., Takayama, M., Abe, Y., & Hirose, N. (2011) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.7039 · Cited by 78 · see citing works
Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective
Cau, P., Navarro, C. L., Harhouri, K., Roll, P., Sigaudy, S., Kaspi, É., Perrin, S., Sandre‐Giovannoli, A. D., & Lévy, N. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.03.021 · Cited by 75 · see citing works
Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates
Sieprath, T., Corne, T., Nooteboom, M., Grootaert, C., Rajković, A., Buysschaert, B., Robijns, J., Broers, J. L. V., Ramaekers, F. C. S., Koopman, W. J. H., et al. (2015) · Nucleus · doi:10.1080/19491034.2015.1050568 · Cited by 76 · see citing works
“For example, fibroblasts from various lipodystrophy patients as well as cells treated with HIV protease inhibitors demonstrate increased ROS levels.(12) Proteomic and metabolic profiling suggest that this increase may be attributed to dysfunctional mitochondria.”
Background
LMNA Mutations Induce a Non-Inflammatory Fibrosis and a Brown Fat-Like Dystrophy of Enlarged Cervical Adipose Tissue
Béréziat, V., Cervera, P., Dour, C. L., Verpont, M., Dumont, S., Vantyghem, M., Capeau, J., & Vigouroux, C. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.07.049 · Cited by 76 · see citing works
Self-citation
Adult stem cell maintenance and tissue regeneration in the ageing context: the role for A‐type lamins as intrinsic modulators of ageing in adult stem cells and their niches
Pekovic, V., & Hutchison, C. J. (2008) · Journal of Anatomy · doi:10.1111/j.1469-7580.2008.00928.x · Cited by 75 · see citing works
“Moreover, oxidative stress has been implicated in the pathophysiology of lamin A-linked Amyotrophic Quadricipital Syndrome with cardiac involvement and in human FPLD fibroblasts with lamin A/C mutations which undergo p16-dependent senescent arrest (Caron et al. 2007; Charniot et al. 2007).”
Background
Defective nuclear import of Tpr in Progeria reflects the Ran sensitivity of large cargo transport
Snow, C. J., Dar, A., Dutta, A., Kehlenbach, R. H., & Paschal, B. M. (2013) · The Journal of Cell Biology · doi:10.1083/jcb.201212117 · Cited by 71 · see citing works
“…with farnesylation of Progerin or inhibit proteolytic processing of pre–lamin A have made it clear that the biological effects of Progerin are strictly dependent on its stable attachment to the nuclear membrane (Capell et al., 2005; Mallampalli et al., 2005; Young et al., 2005; Caron et al., 2007).”
HIV protease inhibitors induce senescence and alter osteoblastic potential of human bone marrow mesenchymal stem cells: beneficial effect of pravastatin
Hernandez‐Vallejo, S. J., Beaupere, C., Larghero, J., Capeau, J., & Lagathu, C. (2013) · Aging Cell · doi:10.1111/acel.12119 · Cited by 70 · see citing works
“The inhibition of ZMP-STE24 by RTV and LPV results in permanently farnesylated prelamin-A, which has been shown to induce cell senescence (Caron et al., 2007; Coffinier et al., 2007).”
BackgroundMethodInfluentialSelf-citation
Nuclear envelope-related lipodystrophies
Guénantin, A.-C., Briand, N., Bidault, G., Afonso, P., Béréziat, V., Vatier, C., Lascols, O., Caron, M., Capeau, J., & Vigouroux, C. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2013.12.015 · Cited by 67 · see citing works
Self-citation
Proteomic Profiling of Adipose Tissue from Zmpste24−/− Mice, a Model of Lipodystrophy and Premature Aging, Reveals Major Changes in Mitochondrial Function and Vimentin Processing
Peinado, J. R., Quirós, P. M., Pulido, M. R., Mariño, G., Martínez‐Chantar, M. L., Vázquez‐Martínez, R., Freije, J. M. P., López-Otı́n, C., & Malagón, M. M. (2011) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m111.008094 · Cited by 68 · see citing works
“23 (PIs), which inhibit Zmpste24 activity and lead to prelamin A accumulation (51), induce the expression of oxidative stress markers in adipose tissue in a manner comparable to that observed in patients with LMNA mutations (52).”
BackgroundResult
Mass spectrometry captures off-target drug binding and provides mechanistic insights into the human metalloprotease ZMPSTE24
Mehmood, S., Marcoux, J., Gault, J., Quigley, A., Michaelis, S., Young, S. G., Carpenter, E. P., & Robinson, C. V. (2016) · Nature Chemistry · doi:10.1038/nchem.2591 · Cited by 65 · see citing works
“Western blot studies show an accumulation of prelamin A in adipose tissue of HIV patients treated with an HIV-PI 39 , suggesting that HIV-PIs do inhibit ZMPSTE24 processing, but a more recent study did not find a significant effect of HIV-PIs on prelamin A processing in peripheral blood mononuclear cells 20 .”
Influential
Effects of Mechanical Stress and Carvedilol in Lamin A/C–Deficient Dilated Cardiomyopathy
Chandar, S., Yeo, L. S., Leimena, C., Tan, J.-C., Xiao, X.-H., Nikolova-Krstevski, V., Yasuoka, Y., Gardiner‐Garden, M., Wu, J., Kesteven, S. H., et al. (2009) · Circulation Research · doi:10.1161/circresaha.109.204388 · Cited by 64 · see citing works
A Potent HIV Protease Inhibitor, Darunavir, Does Not Inhibit ZMPSTE24 or Lead to an Accumulation of Farnesyl-prelamin A in Cells
Coffinier, C., Hudon, S. E., Lee, R., Farber, E., Nobumori, C., Miner, J. H., Andres, D., Spielmann, H. P., Hrycyna, C. A., Fong, L. G., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709629200 · Cited by 64 · see citing works
The p.R482W substitution in A-type lamins deregulates SREBP1 activity in Dunnigan-type familial partial lipodystrophy
Vadrot, N., Duband‐Goulet, I., Cabet, É., Attanda, W., Barateau, A., Vicart, P., Gerbal, F., Briand, N., Vigouroux, C., Oldenburg, A. R., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu728 · Cited by 64 · see citing works
“On one hand, FPLD2 patient fibroblasts prematurely enter senescence (55) and on the other hand, increased SREBP1 activity (due to ectopicmature SREBP1 overexpression) induces increased lipogenesis and triggers senescence in normal human fibroblasts (56).”
BackgroundSelf-citation
HIV protease inhibitors activate the adipocyte renin angiotensin system
Boccara, F., Auclair, M., Cohen, A. A., Lefevre, C., Prot, M., Bastard, J., Capeau, J., & Caron, M. (2009) · Antiviral Therapy · doi:10.3851/imp1533 · Cited by 62 · see citing works
“Cells were cultured and differentiated in 96-well plates, washed and incubated with CM-H2DCFDA (9 µM) or Hoechst 33258 (0.01 µg/ml; Sigma– Aldrich) for 20 min at 37°C in the dark.”
BackgroundMethodInfluentialSelf-citation
Constitutive heterochromatin: a surprising variety of expressed sequences
Dimitri, P., Caizzi, R., Giordano, E., Accardo, M. C., Lattanzi, G., & Biamonti, G. (2009) · Chromosoma · doi:10.1007/s00412-009-0211-y · Cited by 62 · see citing works
“This is probably linked to increased sensitivity to stress of HGPS cells (Caron et al. 2007).”
Background
Lamins as mediators of oxidative stress
Sieprath, T., Darwiche, R., & Vos, W. H. D. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.04.058 · Cited by 61 · see citing works
LMNA mutations resulting in lipodystrophy and HIV protease inhibitors trigger vascular smooth muscle cell senescence and calcification: Role of ZMPSTE24 downregulation
Afonso, P., Auclair, M., Boccara, F., Vantyghem, M., Katlama, C., Capeau, J., Vigouroux, C., & Caron, M. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.12.012 · Cited by 60 · see citing works
“In addition, PI-induced farnesylated prelamin A accumulation was associated with cellular dysfunction and senescence in several cellular models [10, 24-26].”
BackgroundMethodInfluentialSelf-citation
Mitochondria, Bioenergetics, and the Epigenome in Eukaryotic and Human EvolutionPreprint
Wallace, D. C. (2009) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2009.74.031 · Cited by 59 · see citing works
“That these phenotypes are generated by bioenergetic dysfunction is supported by the report that cells harboring LMNA mutations exhibit mitochondrial biochemical defects (Caron et al. 2007; Wallace and Fan 2009a).”
Background
Prelamin A accumulation in endothelial cells induces premature senescence and functional impairment
Bonello‐Palot, N., Simoncini, S., Robert, S., Bourgeois, P., Sabatier, F., Lévy, N., Dignat‐George, F., & Badens, C. (2014) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.08.036 · Cited by 58 · see citing works
Inner nuclear membrane proteins: impact on human disease
Méndez-López, I., & Worman, H. J. (2012) · Chromosoma · doi:10.1007/s00412-012-0360-2 · Cited by 59 · see citing works
“Some studies have also shown that cells with LMNA mutations that cause partial lipodystrophy lead to increased cellular susceptibility to oxidative stress (Caron et al. 2007; Verstraeten et al. 2009).”
Background
Site-dependent differences in both prelamin A and adipogenic genes in subcutaneous adipose tissue of patients with type 2 familial partial lipodystrophy
Araújo‐Vilar, D., Lattanzi, G., González‐Méndez, B., Costa‐Freitas, A. T., Prieto, D., Columbaro, M., Mattioli, E., Victoria, B., Martínez‐Sánchez, N., Рамазанова, А. Р., et al. (2008) · Journal of Medical Genetics · doi:10.1136/jmg.2008.059485 · Cited by 58 · see citing works
Structure and unique mechanical aspects of nuclear lamin filaments
Kronenberg‐Tenga, R., & Medalia, O. (2020) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2020.06.017 · Cited by 56 · see citing works
“Laminopahties are highly varied and include muscular dystrophies [19], lipodystrophies [20] and progeria syndromes [21] to name a few.”
Background
ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders
Barrowman, J., & Michaelis, S. (2009) · Biological Chemistry · doi:10.1515/bc.2009.080 · Cited by 55 · see citing works
“Prelamin A accumulation can be found in the tissues of patients taking HIV-PIs, suggesting a link between inhibition of ZMPSTE24 and the side effects of the drugs (Caron et al., 2007).”
Background
Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome
Donadille, B., D’anella, P., Auclair, M., Uhrhammer, N. A., Sorel, M., Grigorescu, R., Ouzounian, S., Cambonie, G., Boulot, P., Laforêt, P., et al. (2013) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-8-106 · Cited by 56 · see citing works
“R482W LMNAmutated cells [15], was not detectable in control and patient 1’s cells (Figure 6B).”
BackgroundMethodInfluentialSelf-citation
Resveratrol protects against protease inhibitor-induced reactive oxygen species production, reticulum stress and lipid raft perturbation
Touzet, O., & Philips, A. (2010) · AIDS · doi:10.1097/qad.0b013e32833a6114 · Cited by 56 · see citing works
“Nelfinavir induces oxidative stress and can also lead to adipocyte necrosis [43] and premature senescence in human fibroblasts [34].”
Background
One‐year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes
Vatier, C., Fetita, S., Boudou, P., Tchankou, C., Deville, L., Riveline, J., Young, J., Mathivon, L., Travert, F., Morin, D., et al. (2015) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12606 · Cited by 56 · see citing works
“The present results show that metreleptin therapy also increases insulin secretion in this subgroup of patients, affected by typical Dunnigan syndrome (familial partial lipodystrophy 2) [17] or by previously described mixed laminopathic phenotypes associated with lipodystrophic syndrome and progeroid or cardiomyopathi…”
ResultSelf-citation
The struggle of a good friend getting old: cellular senescence in viral responses and therapy
Kohli, J., Veenstra, I., & Demaria, M. (2021) · The EMBO Reports · doi:10.15252/embr.202052243 · Cited by 52 · see citing works
“Prelamin A accumulation is observed in AVTIS cells induced by protease inhibitors but senescence induction was less efficient when cells were also treated with protein farnesylation inhibitors pravastatin or zoledronic acid (Caron et al , 2007; Lef (cid”
Global crotonylome reveals hypoxia-mediated lamin A crotonylation regulated by HDAC6 in liver cancer
Zhang, D., Tang, J. P., Xu, Y., Huang, X., Wang, Y., Jin, X., Wu, G., & Liu, P. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05165-1 · Cited by 54 · see citing works
“Most of these mutations result in the maturation dysfunction and accumulation of prelamin A at the nuclear envelope [24], eventually causing impaired DNA damage repair, cellular senescence, and dysfunction [25–27].”
Background
Prelamin A accumulation and stress conditions induce impaired Oct-1 activity and autophagy in prematurely aged human mesenchymal stem cell
Infante, A., Gago, A., de Eguino, G. R., Calvo-Fernández, T., Gómez‐Vallejo, V., Llop, J., Schlangen, K., Fullaondo, A., Aransay, A. M., Martín, A., et al. (2014) · Aging · doi:10.18632/aging.100651 · Cited by 53 · see citing works
“It has been previously described in the literature that the accumulation of prelamin A induced by some HIV protease inhibitors leads to a premature senescent phenotype in several cell types, including fibroblasts [47], endothelial or peripheral blood mononuclear cells [48].”
Background
Requirements for Efficient Proteolytic Cleavage of Prelamin A by ZMPSTE24
Barrowman, J., Hamblet, C., Kane, M. S., & Michaelis, S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0032120 · Cited by 53 · see citing works
Nuclear Lamins and Oxidative Stress in Cell Proliferation and Longevity
Shimi, T., & Goldman, R. D. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-1-4899-8032-8_19 · Cited by 50 · see citing works
“Fibroblasts derived from patients with the LMNA mutations D47Y, L92F, L387V, R399H, L421P, and R482W, causing insulin resistance and/or lipodystrophy, accumulate pre-LA, and this is related to increased oxidative stress and the decreased expression of mitochondrial respiratory chain proteins that trigger premature cel…”
Background
The induction of a nucleoplasmic reticulum by prelamin A accumulation requires CTP:phosphocholine cytidylyltransferase-α
Goulbourne, C. N., Malhas, A. N., & Vaux, D. J. (2011) · Journal of Cell Science · doi:10.1242/jcs.091009 · Cited by 50 · see citing works
“The consequences of accumulation of farnesylated prelamin A, whether as a result of drug treatment or mutation, has sparked much interest in several areas of cell biology including HIV therapy (Capeau et al., 2006; Capeau et al., 2005; Caron et al., 2007; Clarke, 2007; Coffinier et al., 2007; Coffinier et al., 2008; G…”
Background
Contribution of Adipose Tissue to the Chronic Immune Activation and Inflammation Associated With HIV Infection and Its Treatment
Bourgeois, C., Gorwood, J., Olivo, A., Pelletier, L., Capeau, J., Lambotte, O., Béréziat, V., & Lagathu, C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.670566 · Cited by 49 · see citing works
Self-citation
A Homozygous Mutation of Prelamin-A Preventing Its Farnesylation and Maturation Leads to a Severe Lipodystrophic Phenotype: New Insights into the Pathogenicity of Nonfarnesylated Prelamin-A
Dour, C. L., Schneebeli, S., Bakiri, F., Darcel, F., Jacquemont, M., Maubert, M.-A., Auclair, M., Jeziorowska, D., Reznik, Y., Béréziat, V., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-2234 · Cited by 48 · see citing works
Self-citation
A pathway linking oxidative stress and the Ran GTPase system in progeria
Datta, S., Snow, C. J., & Paschal, B. M. (2014) · Molecular Biology of the Cell · doi:10.1091/mbc.e13-07-0430 · Cited by 47 · see citing works
“LPV is used clinically to inhibit the HIV protease, but it also inhibits Zmpste24, the protease responsible for proteolytic processing of pre–lamin A (Caron et al., 2007; Coffinier et al., 2007; Lefèvre et al., 2010).”
Method
A-type lamins and Hutchinson-Gilford progeria syndrome: pathogenesis and therapy
Jose, M. G. (2011) · Frontiers in Bioscience-Scholar · doi:10.2741/216 · Cited by 46 · see citing works
“Cellular senescence is also increased by treatment with inhibitors of the human immunodeficiency virus protease that also inhibit Zmpste24, resulting in accumulation of farnesylated prelamin A (93).”
Background
Senolytics: Potential for Alleviating Diabetes and Its Complications
Palmer, A. K., Tchkonia, T., & Kirkland, J. L. (2021) · Endocrinology · doi:10.1210/endocr/bqab058 · Cited by 49 · see citing works
“Similarly, individuals with some progeroid syndromes such as those associated with lamin-A (LMNA) mutations, which involve increased senescent cell burden, are also associated with lipodystrophy, metabolic syndrome, and diabetes (21, 22).”
Background
Nuclear damages and oxidative stress: new perspectives for laminopathies
Lattanzi, G., Marmiroli, S., Facchini, A., & Maraldi, N. M. (2012) · European Journal of Histochemistry · doi:10.4081/ejh.2012.e45 · Cited by 45 · see citing works
Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning
Pellegrini, C., Columbaro, M., Schena, E., Prencipe, S., Andrenacci, D., Iozzo, P., Guzzardi, M. A., Capanni, C., Mattioli, E., Loi, M., et al. (2019) · Experimental & Molecular Medicine · doi:10.1038/s12276-019-0289-0 · Cited by 44 · see citing works
The R439C mutation in LMNA causes lamin oligomerization and susceptibility to oxidative stress
Verstraeten, V. L. R. M., Caputo, S. M., Steensel, M. A. M. V., Duband‐Goulet, I., Zinn‐Justin, S., Kamps, M. A. F., Kuijpers, H. J. H., Östlund, C., Worman, H. J., Briedé, J. J., et al. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00690.x · Cited by 43 · see citing works
“In particular, high levels of ROS, mostly produced by the mitochondria, were encountered in fibroblasts from patients with an LMNA-associated lipodystrophy [13].”
Influential
HIV protease inhibitors elicit volume-sensitive Cl− current in cardiac myocytes via mitochondrial ROS
Deng, W., Baki, L., Yin, J., Zhou, H., & Baumgarten, C. M. (2010) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2010.08.013 · Cited by 43 · see citing works
Impact of Darunavir, Atazanavir and Lopinavir Boosted with Ritonavir on Cultured Human Endothelial Cells: Beneficial Effect of Pravastatin
Auclair, M., Afonso, P., Capel, E., Caron-Debarle, M., & Capeau, J. (2014) · Antiviral Therapy · doi:10.3851/imp2752 · Cited by 42 · see citing works
“Senescence Cell senescence was evaluated by the senescenceassociated (SA)-b-galactosidase activity, the protein expression of the senescence markers phospho-p53, p21WAF-1 and p16INK4, and the accumulation of prelamin A, as described previously [29,34].”
MethodSelf-citation
A nuclear lamina‐chromatin‐Ran GTPase axis modulates nuclear import and DNA damage signaling
Dworak, N. M., Mąkosa, D., Chatterjee, M., Jividen, K., Yang, C., Snow, C. J., Simke, W. C., Johnson, I. G., Kelley, J. B., & Paschal, B. M. (2018) · Aging Cell · doi:10.1111/acel.12851 · Cited by 41 · see citing works
“LPV treatment results in the accumulation of unprocessed, nuclear membrane‐tethered preLamin A (Caron et al., 2007).”
Background
Senescent cells at the crossroads of aging, disease, and tissue homeostasis
Kuehnemann, C., & Wiley, C. D. (2023) · Aging Cell · doi:10.1111/acel.13988 · Cited by 41 · see citing works
“…are treated with the HIV PIs indinavir or nelfinavir, or a combination of atazanavir and ritonavir, they accumulate prelamin A and senescence phenotypes (Caron et al., 2007; Kuehnemann et al., 2023), potentially linking these therapies to senescent cells associated with progeroid disorders.”
Background
Mutations in LMNA Modulate the Lamin A - Nesprin-2 Interaction and Cause LINC Complex Alterations
Liu, Y., Munck, M., Swaminathan, K., Kapinos, L. E., Noegel, A. A., & Neumann, S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071850 · Cited by 40 · see citing works
Sp1 Transcription Factor Interaction with Accumulated Prelamin A Impairs Adipose Lineage Differentiation in Human Mesenchymal Stem Cells: Essential Role of Sp1 in the Integrity of Lipid Vesicles
de Eguino, G. R., Infante, A., Schlangen, K., Aransay, A. M., Fullaondo, A., Soriano‐Navarro, M., García‐Verdugo, J. M., Martín, Á. G., & Rodrı́guez, C. I. (2012) · Stem Cells Translational Medicine · doi:10.5966/sctm.2011-0010 · Cited by 40 · see citing works
Prelamin A processing, accumulation and distribution in normal cells and laminopathy disorders
Casasola, A., Scalzo, D., Nandakumar, V., Halow, J. M., Targa, F. R., Groudine, M. T., & Rincón‐Arano, H. (2016) · Nucleus · doi:10.1080/19491034.2016.1150397 · Cited by 39 · see citing works
“The antibody described here is also a particularly useful tool for the study of prelamin A in progeroid laminopathies, metabolic laminopathies and lipodystrophies.(33,54,57,58,67) Several reports support the involvement of farnesylated prelamin A in these disorders.”
Lipodystrophic syndromes due to LMNA mutations: recent developments on biomolecular aspects, pathophysiological hypotheses and therapeutic perspectives
Vigouroux, C., Guénantin, A.-C., Vatier, C., Capel, E., Dour, C. L., Afonso, P., Bidault, G., Béréziat, V., Lascols, O., Capeau, J., et al. (2018) · The Nucleus · doi:10.1080/19491034.2018.1456217 · Cited by 37 · see citing works
Self-citation
A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy
Galant, D., Gaborit, B., Desgrouas, C., Abdesselam, I., Bernard, M., Lévy, N., Merono, F., Coirault, C., Roll, P., Lagarde, A., et al. (2016) · Cells · doi:10.3390/cells5020021 · Cited by 38 · see citing works
“Nevertheless, we showed that the patient’s cells exhibit accelerated senescence and that the senescence rate is similar to the rate observed for fibroblasts carrying the R482W LMNA mutation, responsible for the FPL Dunnigan Type [27].”
Result
SIV Infection and the HIV Proteins Tat and Nef Induce Senescence in Adipose Tissue and Human Adipose Stem Cells, Resulting in Adipocyte Dysfunction
Gorwood, J., Ejlalmanesh, T., Bourgeois, C., Mantecon, M., Rose, C., Atlan, M., Desjardins, D., Grand, R. L., Fève, B., Lambotte, O., et al. (2020) · Cells · doi:10.3390/cells9040854 · Cited by 38 · see citing works
“First generation PIs induced cellular senescence in fibroblasts [17], endothelial cells [56–58], and in smooth muscle cells [15].”
BackgroundSelf-citation
What the Genetics of Lipodystrophy Can Teach Us About Insulin Resistance and Diabetes
Vatier, C., Bidault, G., Briand, N., Guénantin, A.-C., Salle-Teyssières, L., Lascols, O., Capeau, J., & Vigouroux, C. (2013) · Current Diabetes Reports · doi:10.1007/s11892-013-0431-7 · Cited by 37 · see citing works
Self-citation
Prelamin A is involved in early steps of muscle differentiation
Capanni, C., Coco, R. D., Squarzoni, S., Columbaro, M., Mattioli, E., Camozzi, D., Rocchi, A., Scotlandi, K., Maraldi, N. M., Foisner, R., et al. (2008) · Experimental Cell Research · doi:10.1016/j.yexcr.2008.09.026 · Cited by 37 · see citing works
The Cutting Edge: The Role of mTOR Signaling in Laminopathies
Chiarini, F., Evangelisti, C., Cenni, V., Fazio, A., Paganelli, F., Martelli, A. M., & Lattanzi, G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20040847 · Cited by 35 · see citing works
“gov/pmc/articles/PMC6412338/ 22/48 At the molecular level, FPLD2, MADA, and MADB are also characterized by accumulation of prelamin A at the nuclear periphery [66,126].”
Background
The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor
Lacombe, M., Lamarche, F., Wever, O. D., Padilla‐Benavides, T., Carlson, A., Khan, I., Huna, A., Vacher, S., Calmel, C., Desbourdes, C., et al. (2021) · BMC Biology · doi:10.1186/s12915-021-01155-5 · Cited by 35 · see citing works
Deregulation of Fragile X-related protein 1 by the lipodystrophic lamin A p.R482W mutation elicits a myogenic gene expression program in preadipocytes
Oldenburg, A. R., Delbarre, E., Thiede, B., Vigouroux, C., & Collas, P. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt509 · Cited by 35 · see citing works
“Disruption of the lamin A–FXR1P interaction by the R482W mutation, and displacement of FXR1P from the nucleus in FPLD2 cells, could be due to pre-lamin A expression in these cells (46,47) and steric inhibition of mature lamin A-FXR1P interaction at the NE.”
BackgroundSelf-citation
Warburg effect linked to cognitive‐executive deficits in FMR1 premutation
Napoli, E., Song, G., Schneider, A., Hagerman, R. J., Eldeeb, M. A. A. A., Azarang, A., Tassone, F., & Giulivi, C. (2016) · The FASEB Journal · doi:10.1096/fj.201600315r · Cited by 34 · see citing works
“In this regard,mitochondrial defects have been reported in carriers of lamin A pathogenic mutations along with increased oxidative stress, decreased DNA repair response, and premature cellular aging (87, 88), similar to the lamin A/C dysregulation reported in carriers of the premutation (89).”
Background
Bone imaging findings in genetic and acquired lipodystrophic syndromes: an imaging study of 24 cases
Teboul-Coré, S., Rey-Jouvin, C., Miquel, A., Vatier, C., Capeau, J., Robert, J., Pham, T., Lascols, O., Berenbaum, F., Larédo, J.-D., et al. (2016) · Skeletal Radiology · doi:10.1007/s00256-016-2457-9 · Cited by 33 · see citing works
“Interestingly, we observed in our study that patients with FPLD had frequently non-specific degenerative joint and tendons abnormalities, which could be favored by insulin resistance and diabetes and/or by the premature cellular senescence associated with LMNA mutations [30].”
BackgroundSelf-citation
Antiretroviral‐Related Adipocyte Dysfunction and Lipodystrophy in HIV‐Infected Patients: Alteration of the PPARγ‐Dependent Pathways
Caron, M., Vigouroux, C., Bastard, J., & Capeau, J. (2008) · PPAR Research · doi:10.1155/2009/507141 · Cited by 32 · see citing works
“When going further into the mechanism of PI action, we and others demonstrated that some PIs prevented the maturation of lamin A/C [22, 34, 78], a nuclear membrane protein essential for normal nuclear membrane folding and for nuclear penetration of SREBP-1 [59, 79, 80].”
BackgroundSelf-citation
Impaired nuclear functions lead to increased senescence and inefficient differentiation in human myoblasts with a dominant p.R545C mutation in the LMNA gene
Kandert, S., Wehnert, M. S., Müller, C. R., Buendia, B., & Dabauvalle, M. (2009) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2009.06.002 · Cited by 33 · see citing works
Human CaaX protease ZMPSTE 24 expressed in yeast: Structure and inhibition by HIV protease inhibitors
Clark, K. M., Jenkins, J. L., Fedoriw, N., & Dumont, M. E. (2016) · Protein Science · doi:10.1002/pro.3074 · Cited by 32 · see citing works
LMNA-linked lipodystrophies: from altered fat distribution to cellular alterations
Bidault, G., Vatier, C., Capeau, J., Vigouroux, C., & Béréziat, V. (2011) · Biochemical Society Transactions · doi:10.1042/bst20110675 · Cited by 30 · see citing works
Self-citation
Histological and molecular features of lipomatous and nonlipomatous adipose tissue in familial partial lipodystrophy caused by LMNA mutations
Araújo‐Vilar, D., Victoria, B., González‐Méndez, B., Barreiro, F. J. J., Fernández‐Rodríguez, B., Cereijo, R., Gallego-Escuredo, J. M., Villarroya, F., & Pañeda‐Menéndez, A. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2011.04208.x · Cited by 31 · see citing works
Nuclear Nox4 interaction with prelamin A is associated with nuclear redox control of stem cell aging
Casciaro, F., Beretti, F., Zavatti, M., McCubrey, J. A., Ratti, S., Marmiroli, S., Follo, M. Y., & Maraldi, T. (2018) · Aging · doi:10.18632/aging.101599 · Cited by 30 · see citing works
“Various studies revealed not only that ROS levels are increased in laminopathy patient cells and during prelamin A accumulation, but also that this increase may be attributed to dysfunctional mitochondria [15-18].”
Antiretroviral protease inhibitors induce features of cellular senescence that are reversible upon drug removal
Kuehnemann, C., Hughes, J. B., Desprez, P., Melov, S., Wiley, C. D., & Campisi, J. (2022) · Aging Cell · doi:10.1111/acel.13750 · Cited by 27 · see citing works
Keratins Are Altered in Intestinal Disease-Related Stress Responses
Helenius, T. O., Antman, C., Asghar, M. N., Nyström, J. H., & Toivola, D. M. (2016) · Cells · doi:10.3390/cells5030035 · Cited by 28 · see citing works
“Glial fibrillary acidic protein (GFAP) is upregulated in the oxidative stress reaction in response to brain injury [57], vimentin is three-fold upregulated in senescent fibroblasts [58] and lamin A is upregulated and accumulated in premature cellular senescence [59].”
Background
Different prelamin A forms accumulate in human fibroblasts: a study in experimental models and progeria
Dominici, S., Fiori, V., Magnani, M., Schena, E., Capanni, C., Camozzi, D., D’Apice, M., Dour, C. L., Auclair, M., Caron, M., et al. (2009) · European Journal of Histochemistry · doi:10.4081/ejh.2009.e6 · Cited by 28 · see citing works
“Moreover, they can be used to monitor the effects of drugs acting on prelamin A processing, which are potential therapeutic tools in laminopathies featuring prelamin A accumulation (Caron et al., 2007) and in cancer therapy (Adjei et al., 2000; Ramirez et al., 2007).”
InfluentialSelf-citation
Prelamin A-mediated nuclear envelope dynamics in normal and laminopathic cells
Lattanzi, G. (2011) · Biochemical Society Transactions · doi:10.1042/bst20110657 · Cited by 27 · see citing works
The Interplay between Oxidative Stress and the Nuclear Lamina Contributes to Laminopathies and Age-Related Diseases
Kristiani, L., & Kim, Y. (2023) · Cells · doi:10.3390/cells12091234 · Cited by 26 · see citing works
“The expression of cytochrome c oxidase subunit II (COX 2) is drastically decreased in human fibroblasts and adipocytes bearing lamin A variants, which lowers mitochondrial membrane potential and generates excessive ROS [34].”
Background

LMNA missense mutations causing familial partial lipodystrophy do not lead to an accumulation of prelamin A
Tu, Y., Sánchez‐Iglesias, S., Araújo‐Vilar, D., Fong, L. G., & Young, S. G. (2016) · Nucleus · doi:10.1080/19491034.2016.1242542 · Cited by 13 · see citing works
A Homozygous Mutation of Prelamin-A Preventing Its Farnesylation and Maturation Leads to a Severe Lipodystrophic Phenotype: New Insights into the Pathogenicity of Nonfarnesylated Prelamin-A
Dour, C. L., Schneebeli, S., Bakiri, F., Darcel, F., Jacquemont, M., Maubert, M.-A., Auclair, M., Jeziorowska, D., Reznik, Y., Béréziat, V., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-2234 · Cited by 48 · see citing works
Self-citation
A Rare Mutation in LMNB2 Associated with Lipodystrophy Drives Premature Cell Senescence
Varlet, A., Desgrouas, C., Jebane, C., Bonello‐Palot, N., Bourgeois, P., Lévy, N., Helfer, E., Dubois, N., Valéro, R., Badens, C., et al. (2021) · Cells · doi:10.3390/cells11010050 · Cited by 7 · see citing works
Lipodystrophic syndromes due to LMNA mutations: recent developments on biomolecular aspects, pathophysiological hypotheses and therapeutic perspectives
Vigouroux, C., Guénantin, A.-C., Vatier, C., Capel, E., Dour, C. L., Afonso, P., Bidault, G., Béréziat, V., Lascols, O., Capeau, J., et al. (2018) · The Nucleus · doi:10.1080/19491034.2018.1456217 · Cited by 37 · see citing works
Self-citation
LMNA Mutations Induce a Non-Inflammatory Fibrosis and a Brown Fat-Like Dystrophy of Enlarged Cervical Adipose Tissue
Béréziat, V., Cervera, P., Dour, C. L., Verpont, M., Dumont, S., Vantyghem, M., Capeau, J., & Vigouroux, C. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.07.049 · Cited by 76 · see citing works
Self-citation

Authors: Caron, M., Auclair, M., Donadille, B., Béréziat, V, Guerci, B., Laville, M., Narbonne, H., Bodemer, C., Lascols, O., Capeau, J., & Vigouroux, C.
Affiliations: Inserm (FR)
Centre Hospitalier Régional et Universitaire de Nancy (FR)
Hospices Civils de Lyon (FR)
Assistance Publique Hôpitaux de Marseille (FR)
Hôpital Necker-Enfants Malades (FR)
Corresponding author: Caron, M
ORCID: Auclair, M
Donadille, B
Béréziat, V
Guerci, B
Laville, M
Bodemer, C
Capeau, J
Vigouroux, C
Venue: Cell Death & Differentiation
Publisher: Springer Science and Business Media LLC
Published: 2007-07-06
Volume: 14
Issue: 10
Pages: 1759-1767
ISSN: 1350-9047 (ISSN-L)
1476-5403
DOI: 10.1038/sj.cdd.4402197
OpenAlex: W1979927283
Cited by: 226
References: 45
Citations by year: 2026: 2 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 12 · 2021: 33 · 2020: 8 · 2019: 7 · 2018: 7 · 2017: 9 · 2016: 15 · 2015: 9 · 2014: 12 · 2013: 17 · 2012: 10
FWCI: 6.22
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Cell Death and Differentiation (publishedVersion)
PubMed (publishedVersion)
Funders: Styrelsen för Internationellt Utvecklingssamarbete
Sidaction
European Commission
Institut National de la Santé et de la Recherche Médicale
Servier
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Health Sciences › Medicine › Emergency Medicine › HIV-related health complications and treatments
Keywords: lipodystrophy, LMNA mutations, A-type lamins, HIV protease inhibitors, oxidative stress, premature aging, farnesylation, p16, mitochondrial respiratory chain, nuclear abnormalities, fibroblasts, adipose tissue
MeSH terms: Adult, Biopsy, Cells, Cultured, Child, Female, Fibroblasts, Humans, Middle Aged, Mitochondria, Mutation, Nuclear Proteins, Protein Precursors, Cellular Senescence, HIV Protease Inhibitors, Reactive Oxygen Species, Oxidative Stress, Indinavir, Nelfinavir, Cyclin-Dependent Kinase Inhibitor p16, Lamin Type A, Cyclin-Dependent Kinase Inhibitor p21, Lipodystrophy, Familial Partial, Cell Nucleus Shape

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Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence

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