Project description
Cell components contributing to mitochondrial dysfunction
Mitochondrial electron transport chain (ETC) defects underlie biochemical failure and pathologies associated with mitochondrial dysfunction. The EU-funded MitoCure project proposes a comprehensive study of the molecular and metabolic components that contribute to cell and tissue deterioration in the case of ETC dysfunction. The goals are to identify genes controlling the function and integrity of ETC complexes, to define how ETC dysfunction impacts cellular metabolism, with a special focus on redox-sensitive pathways, and elucidate brain-specific signalling that impacts mitochondrial dysfunction. The MitoCure is an ambitious project to obtain novel information about genes, metabolic pathways and signalling mechanisms underlying the pathophysiology associated with mitochondrial dysfunction.
Objective
Mitochondria are essential organelles that carry out critical metabolic functions within the cells. Electron transport chain (ETC) defects occurring from mitochondrial disease mutations compromise cellular fitness and survival. This biochemical failure is thought to underlie pathologies associated with mitochondrial dysfunction. However, the precise metabolic processes, signaling pathways and compensatory responses resulting from a defective mitochondrial ETC that drive these fatal disorders are not entirely understood. Although diminished ATP production has been considered a hallmark of mitochondrial dysfunction, I hypothesize that other metabolic failures such as disturbed redox hemostasis due to accumulated levels of NADH can be equally detrimental. Moreover, which cell types contribute the most to the disease and whether disease-carrying cells negatively impact the function of its surrounding wild-type neighbors or distant organs remain poorly characterized. Here I propose to develop a holistic understanding of the molecular and metabolic components that contribute to cell and tissue deterioration in the context of ETC dysfunction. Our central goals are: (1) To identify novel uncharacterized genes controlling function and integrity of ETC complexes and supercomplexes (2) To define how ETC dysfunction impacts cellular metabolism with special focus on redox-sensitive pathways that might be altered as a consequence of imbalanced NAD+/NADH ratio (3) To elucidate brain-specific non cell-autonomous signaling that mediates maladaptation to mitochondrial dysfunction. In sum, MitoCure puts forward an ambitious but feasible program with the purpose of yielding novel information about genes, metabolic pathways and signaling mechanisms underlying the pathophysiology associated with mitochondrial dysfunction.
Fields of science
Programme(s)
Topic(s)
Funding Scheme
ERC-STG - Starting GrantHost institution
28049 Madrid
Spain