GLOBAL ANALYSIS OF MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS IN DOWN’S SYNDROME

HELGUERA P; BUSCIGLIO J

Paris

Conferencia; International conference Jerome Lejeune; 2011

Institute Pasteur

<!-- /* Font Definitions */ @font-face {font-family:Arial; panose-1:2 11 6 4 2 2 2 2 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin-top:0in; margin-right:0in; margin-bottom:10.0pt; margin-left:0in; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:Cambria; mso-fareast-theme-font:minor-latin; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} @page Section1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.Section1 {page:Section1;} --> <!-- /* Font Definitions */ @font-face {font-family:Arial; panose-1:2 11 6 4 2 2 2 2 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin-top:0in; margin-right:0in; margin-bottom:10.0pt; margin-left:0in; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:Cambria; mso-fareast-theme-font:minor-latin; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} @page Section1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.Section1 {page:Section1;} --> Down´s syndrome (DS) individuals show a high prevalence of chronic disorders including obesity, diabetes and Alzheimer’s disease. Previous work indicates that altered mitochondrial function leads to persistent deficits on cell capability and viability.  Then, mitochondrial dysfunction may be a critical element of DS pathology, as it is of type 2 diabetes and AD.  Structural and functional alterations exist in mitochondria of several primary cell types in DS.  For example, cultured islet cell clusters (ICC) present loss of mitochondrial membrane potential, decreased ATP production, reduced oxidoreductase activity and altered mitochondrial dynamics. Insulin levels are decreased, while pro-insulin levels are increased in DS ICC. These alterations can be partially reverted by antioxidants and mitochondrial cofactors. However, under rescuing conditions, DS cells show high levels of superoxide, lipid peroxidation and reduced viability. Transcriptome and network analysis of genes specifically overexpressed in DS demonstrate functional integration in signaling pathways involved in mitochondrial dysfunction, oxidative stress and oxidative stress-related gene response. Similar expression changes occur in normal cells under chronic oxidative stress. Thus, reduced mitochondrial activity in DS cells may represent an adaptive response to oxidative stress that paradoxically compromises cellular metabolism leading to chronic phenotypes usually associated with DS