alexa Identification of mitochondrial dysfunction in Hutchinson-Gilford progeria syndrome through use of stable isotope labeling with amino acids in cell culture.
Genetics & Molecular Biology

Genetics & Molecular Biology

Journal of Genetic Syndromes & Gene Therapy

Author(s): RiveraTorres J, AcnPerez R, CabezasSnchez P, Osorio FG, GonzalezGmez C,

Abstract Share this page

Abstract Hutchinson-Gilford progeria syndrome (HGPS) is a rare segmental premature aging disorder that recapitulates some biological and physical aspects of physiological aging. The disease is caused by a sporadic dominant mutation in the LMNA gene that leads to the expression of progerin, a mutant form of lamin A that lacks 50 amino acids and retains a toxic farnesyl modification in its carboxy-terminus. However, the mechanisms underlying cellular damage and senescence and accelerated aging in HGPS are incompletely understood. Here, we analyzed fibroblasts from healthy subjects and HGPS patients using SILAC (stable isotope labeling with amino acids in cell culture). We found in HGPS cells a marked downregulation of mitochondrial oxidative phosphorylation proteins accompanied by mitochondrial dysfunction, a process thought to provoke broad organ decline during normal aging. We also found mitochondrial dysfunction in fibroblasts from adult progeroid mice expressing progerin (Lmna(G609G/G609G) knock-in mice) or prelamin A (Zmpste24-null mice). Analysis of tissues from these mouse models revealed that the damaging effect of these proteins on mitochondrial function is time- and dose-dependent. Mitochondrial alterations were not observed in the brain, a tissue with extremely low progerin expression that seems to be unaffected in HGPS. Remarkably, mitochondrial function was restored in progeroid mouse fibroblasts treated with the isoprenylation inhibitors FTI-277 or pravastatin plus zoledronate, which are being tested in HGPS clinical trials. Our results suggest that mitochondrial dysfunction contributes to premature organ decline and aging in HGPS. Beyond its effects on progeria, prelamin A and progerin may also contribute to mitochondrial dysfunction and organ damage during normal aging, since these proteins are expressed in cells and tissues from non-HGPS individuals, most prominently at advanced ages. BIOLOGICAL SIGNIFICANCE: Mutations in LMNA or defective processing of prelamin A causes premature aging disorders, including Hutchinson-Gilford progeria syndrome (HGPS). Most HGPS patients carry in heterozygosis a de-novo point mutation (c.1824C>T: GGC>GGT; p.G608G) which causes the expression of the lamin A mutant protein called progerin. Despite the importance of progerin and prelamin A in accelerated aging, the underlying molecular mechanisms remain largely unknown. To tackle this question, we compared the proteome of skin-derived dermal fibroblast from HGPS patients and age-matched controls using quantitative stable isotope labeling with amino acids in cell culture (SILAC). Our results show a pronounced down-regulation of several components of the mitochondrial ATPase complex accompanied by up-regulation of some glycolytic enzymes. Accordingly, functional studies demonstrated mitochondrial dysfunction in HGPS fibroblasts. Moreover, our expression and functional studies using cellular and animal models confirmed that mitochondrial dysfunction is a feature of progeria which develops in a time- and dose-dependent manner. Finally, we demonstrate improved mitochondrial function in progeroid mouse cells treated with a combination of statins and aminobisphosphonates, two drugs that are being evaluated in ongoing HGPS clinical trials. Although further studies are needed to unravel the mechanisms through which progerin and prelamin A provoke mitochondrial abnormalities, our findings may pave the way to improved treatments of HGPS. These studies may also improve our knowledge of the mechanisms leading to mitochondrial dysfunction during normal aging, since both progerin and prelamin A have been found to accumulate during normal aging. © 2013 Elsevier B.V. All rights reserved. This article was published in J Proteomics and referenced in Journal of Genetic Syndromes & Gene Therapy

Relevant Expert PPTs

Relevant Speaker PPTs

Recommended Conferences

Relevant Topics

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri, Food, Aqua and Veterinary Science Journals

Dr. Krish

agrifoodaquavet@omicsonline.com

1-702-714-7001 Extn: 9040

Clinical and Biochemistry Journals

Datta A

clinical_biochem@omicsonline.com

1-702-714-7001Extn: 9037

Business & Management Journals

Ronald

business@omicsonline.com

1-702-714-7001Extn: 9042

Chemical Engineering and Chemistry Journals

Gabriel Shaw

chemicaleng_chemistry@omicsonline.com

1-702-714-7001 Extn: 9040

Earth & Environmental Sciences

Katie Wilson

environmentalsci@omicsonline.com

1-702-714-7001Extn: 9042

Engineering Journals

James Franklin

engineering@omicsonline.com

1-702-714-7001Extn: 9042

General Science and Health care Journals

Andrea Jason

generalsci_healthcare@omicsonline.com

1-702-714-7001Extn: 9043

Genetics and Molecular Biology Journals

Anna Melissa

genetics_molbio@omicsonline.com

1-702-714-7001 Extn: 9006

Immunology & Microbiology Journals

David Gorantl

immuno_microbio@omicsonline.com

1-702-714-7001Extn: 9014

Informatics Journals

Stephanie Skinner

omics@omicsonline.com

1-702-714-7001Extn: 9039

Material Sciences Journals

Rachle Green

materialsci@omicsonline.com

1-702-714-7001Extn: 9039

Mathematics and Physics Journals

Jim Willison

mathematics_physics@omicsonline.com

1-702-714-7001 Extn: 9042

Medical Journals

Nimmi Anna

medical@omicsonline.com

1-702-714-7001 Extn: 9038

Neuroscience & Psychology Journals

Nathan T

neuro_psychology@omicsonline.com

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

John Behannon

pharma@omicsonline.com

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

social_politicalsci@omicsonline.com

1-702-714-7001 Extn: 9042

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version