1. ¹INSERM, U680, Paris, F-75012 France
2. ²Université Pierre et Marie Curie-Paris6, Faculté de Médecine, UMRS680, Paris, F-75005 France
3. ³Hôpital Jeanne d'Arc, Service de Diabétologie, Endocrinologie et Nutrition, CHU Nancy, France
4. ⁴Centre de recherche en Nutrition Humaine, Hospices Civils, Lyon, France
5. ⁵AP-HM, Hôpital La Timone, Service de Nutrition, Maladies Métaboliques, Endocrinologie, Marseille, France
6. ⁶AP-HP, Hôpital Necker-Enfants Malades, Service de Dermatologie, Paris, France
7. ⁷AP-HP, Hôpital Saint-Antoine, Département de Biologie Moléculaire, Paris, France
8. ⁸AP-HP, Hôpital Tenon, Service de Biochimie et Hormonologie, Paris, France

Correspondence: M Caron, Inserm U680, Faculté de Médecine Pierre et Marie Curie, Site Saint-Antoine, 27 rue Chaligny, 75571 Paris Cedex 12. Tel: +33 1 40 01 14 84; Fax: +33 1 40 01 13 52; E-mail: caron@st-antoine.inserm.fr

Received 11 January 2007; Revised 17 May 2007; Accepted 17 May 2007; Published online 6 July 2007.

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.