Developing next-generation tools for mitochondrial dissection with cell-specific resolution.

Projektinformationen

MitoTAGs

ID Finanzhilfevereinbarung: 658352

DOI

10.3030/658352

Projekt abgeschlossen

EK-Unterschriftsdatum 25 März 2015

Startdatum 1 Mai 2015

Enddatum 30 April 2017

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 170 121,60

EU-Beitrag

€ 170 121,60

Koordiniert durch

UNIVERSITAT AUTONOMA DE BARCELONA
Spain

Periodic Reporting for period 1 - MitoTAGs (Developing next-generation tools for mitochondrial dissection with cell-specific resolution.)

Berichtszeitraum: 2015-05-01 bis 2017-04-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Severe alterations of the mitochondrial machinery involved in energy generation lead to a group of progressive and usually fatal pathologies collectively known as primary mitochondrial disease (MD), affecting 1:5000 births. Currently, there is no cure and the treatments available are mostly ineffective. MD predominantly affects high energy-requiring organs such as the brain. However, not all neurons are equally vulnerable to MD, but rather show a striking anatomical and cellular specificity. The mechanisms conferring neuronal resistance or vulnerability to MD are currently unknown. To date, research in mitochondrial disease has been hindered by the high degree of variability in disease progression and severity in human patients, and the intrinsic heterogeneity of mitochondria. Furthermore, model systems both in vivo and in vitro to date have failed to identify the mechanisms underlying the anatomical and cellular specificity of these pathologies. Hence, if one could possess the ability to identify, purify and compare cellular and mitochondrial changes from affected and healthy neurons, a better and more significant insight on the biochemical and functional changes associated with MD would be obtained. To address this issue, two ground-breaking approaches were developed to define the molecular basis of neuronal susceptibility to mitochondrial disease. These approaches have the potential to propose new therapeutic targets for MD and are easily applicable to other pathologies associated with mitochondrial dysfunction such as diabetes or neurodegenerative processes.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

To improve on current knowledge on mitochondrial disease and to provide better therapeutic targets, two ground-breaking molecular biology tools that will allow the identification and dissection of the molecular determinants of neuronal vulnerability in mitochondrial disease with unprecedented definition were developed. First, a novel tool to isolate the mitochondrial translatome of vulnerable neurons was generated. Next, another tool to isolate whole mitochondria from specific cell types to assess intact mitochondrial function, and allow metabolomic, proteomic or mito-genomic analyses was also successfully developed. The novel tools generated will not be disseminated until their protection through intellectual property (IP) has been accomplished. These tools are currently under a patentability study.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

The application of these methods will have a high impact in the field, allowing for a level of molecular dissection not previously attainable in a physiologically-relevant setting. Furthermore, this degree of resolution will provide novel insight into the determinants of cell survival, or death, in the context of mitochondrial disease, advancing significantly towards our overarching goal of finding novel and better targets with therapeutic potential for this devastating pediatric disease. Furthermore, due to the high applicability and transferability of these approaches, these tools will likely benefit both industry and academic research on diverse pathologies with mitochondrial implications, such as neurodegenerative diseases (i.e. Parkinson, Huntington or Alzheimer disease), metabolic diseases such as diabetes, or cancer. This impact on research will likely have a positive influence on the overall health of our aging society.

Mitochondria (in green) labeled with one of the novel tools generated