title: 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.
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.
authors.affiliation: INSERM U680, Université Pierre et Marie Curie-Paris 6, Faculté de Médecine, Site Saint-Antoine, 27 rue Chaligny, 75571 Paris Cedex 12, France. caron@st-antoine.inserm.fr
authors.forename: M
authors.initials: M
authors.lastname: Caron
authors.forename: M
authors.initials: M
authors.lastname: Auclair
authors.forename: B
authors.initials: B
authors.lastname: Donadille
authors.forename: V
authors.initials: V
authors.lastname: Béréziat
authors.forename: B
authors.initials: B
authors.lastname: Guerci
authors.forename: M
authors.initials: M
authors.lastname: Laville
authors.forename: H
authors.initials: H
authors.lastname: Narbonne
authors.forename: C
authors.initials: C
authors.lastname: Bodemer
authors.forename: O
authors.initials: O
authors.lastname: Lascols
authors.forename: J
authors.initials: J
authors.lastname: Capeau
authors.forename: C
authors.initials: C
authors.lastname: Vigouroux
mesh_terms: D000328:Adult; D001706:Biopsy; D053144:Cell Nucleus Shape; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D002648:Child; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D019469:Indinavir / Q000627:therapeutic use; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D052496:Lipodystrophy, Familial Partial / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008875:Middle Aged; D008928:Mitochondria / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics*; D019888:Nelfinavir / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D011498:Protein Precursors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017320:HIV Protease Inhibitors; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; D017382:Reactive Oxygen Species; C090764:prelamin A; D019469:Indinavir; D019888:Nelfinavir