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Molecular and metabolic mechanisms underlying 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.

Call for proposal

ERC-2020-STG
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Funding Scheme

ERC-STG - Starting Grant

Host institution

UNIVERSIDAD AUTONOMA DE MADRID
Address
Calle Einstein 3 Ciudad Univ Cantoblanco Rectorado
28049 Madrid
Spain
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 463 410

Beneficiaries (1)

UNIVERSIDAD AUTONOMA DE MADRID
Spain
EU contribution
€ 1 463 410
Address
Calle Einstein 3 Ciudad Univ Cantoblanco Rectorado
28049 Madrid
Activity type
Higher or Secondary Education Establishments