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Form and Function of the Mitochondrial Retrograde Response

Project description

Dissecting the mitochondrial quality control process

Mitochondria are key organelles in cellular homeostasis. They produce energy, regulate cell signalling and the biochemical reactions central to metabolism. To meet energy demands and retain their function, mitochondria communicate with the nucleus through a process known as the mitochondrial retrograde response (MRR) enacted by the nuclear transcription factors via mediators such as calcium ion (Ca2+), reactive oxygen species (ROS) and NAD/NADH ratio. The scope of the EU-funded FIRM project is to gain insight into the regulation of the MRR by informing the redistribution on the nucleus of the mitochondria and their cholesterol pools. Apart from providing insights into fundamental cellular mechanisms, researchers are working towards targeting the MRR process for diagnostic and therapeutic applications for diseases involving mitochondrial dysfunction.

Objective

The molecular communication between mitochondria and nucleus is an integrated bi-directional crosstalk - anterograde (nucleus to mitochondria) and retrograde (mitochondria to nucleus) signalling pathways. The mitochondrial retrograde response (MRR) is driven by defective mitochondrial function, which increases cytosolic reactive oxygen species (ROS) and Ca2+. Metabolic reprogramming is a key feature in highly proliferative cells to meet the energy needs for rapid growth by generating substrates for cellular biogenesis. In these mitochondria retro-communicate with the nucleus to induce wide-ranging cytoprotective effects exploited to develop resistance against treatment and sustain uncontrolled growth. Recently, the mitochondrial management of cholesterol-derived intermediates for the synthesis of steroids has been demonstrated as a determinant in the oncogenic reprogramming of cellular environment.
We hypothesise that cholesterol-enriched domains facilitate the communication between remodelled mitochondria and nucleus to expedite MRR. This mechanism may be exploited during abnormal cell growth in which cholesterol metabolism and associated molecules are increased.
This application capitalizes on expertise in cell signalling and metabolism to interrogate core pathways and unveil molecular sensors and effectors that define form and function of the MRR by:
I. Elucidating the mechanism of metabolic regulation of MRR, describing the role exerted by cholesterol trafficking;
II. Unveiling microdomains for mito-nuclear communication established by remodelled, autophagy escaped, mitochondria;
III. Validating protocols to modulate and target MRR for diagnostic and therapeutic benefit;
The experimental plan will (i) define a molecular signalling axis that currently stands uncharacterized, (ii) provide mechanistic knowledge for preventive, and (iii) therapeutic applications to counteract deficiencies associated with stressed, dysregulated mitochondria.

Fields of science (EuroSciVoc)

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Host institution

QUEEN MARY UNIVERSITY OF LONDON
Net EU contribution
€ 878 105,75
Address
327 MILE END ROAD
E1 4NS London
United Kingdom

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Activity type
Higher or Secondary Education Establishments
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Total cost
€ 878 105,75

Beneficiaries (2)

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