The shape of mitochondrial dysfunction in Down Syndrome

Oxidative stress (OS) and mitochondrial dysfunction (MD) have been extensively studied and defined as therapeutic targets in Down syndrome (DS). Though originally associated to individual genes located in supernumerary chromosome 21, OS and MD metabolic compromises appear to be linked to whole genome functionally defined transcriptional fingerprints that further exacerbate the contribution of critical genes in DS–AD pathology. As the main ROS generator, mitochondrial complex double-membrane organization, tightly regulated fission/fusion dynamics, and involvement in critical pathways, makes it particularly vulnerable to functional alterations. Consequently, mitochondrial network morphology depends on its metabolic state and has been used as an indicator of cellular homeostasis. Initial qualitative categorization, suitable for sparse arranged fragments analysis, were proven to be ineffective to measure network connectivity and replaced by innovative tools that involve the transformation of raw images to linear skeletons. These manipulations allowed the development of a new generation of structural parameters, such as mean degree value (MDV). Alterations in DS mitochondrial networks include increased frequency of aberrant morphologies, shorter mitochondrial fragments, and significantly lower mitochondrial network connectivity. Similar structural and functional mitochondrial defects are common to other neurodegenerative diseases, such as Parkinson disease and Prion disease, and to a progeroid syndrome like HGPS. Therapeutic interventions aimed to either increase mitochondrial biogenesis or diminish OS using mitochondrial-targeted antioxidants, successfully restored mitochondrial activity and structural organization, confirming the strong correlation between network form and function.Fil: Zamponi, Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Helguera, Pablo Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentin