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Cellular modulation by the mitochondrial unfolded protein response

Objective

Mitochondrial function is central for cellular metabolism and energy balance. However, many diseases, including cancer and neurodegenerative diseases, affect mitochondrial function and proteostasis. Upon mitochondrial protein misfolding, mitochondria activate the mitochondrial unfolded protein response (UPRmt) to restore proteostasis, a poorly characterized pathway in mammalian cells. Notably, the effects of the UPRmt on its direct environment – mitochondria – and on cytosolic homeostasis remain unknown. Strikingly, non-cell autonomous signaling of metabolism and folding state has been described in recent years, particularly in worms. However, the possible role of UPRmt in such processes is undescribed.
Using newly available tools to acutely induce the UPRmt in mammalian cells, combined with cutting-edge quantitative mass spectrometry, microscopy, next generation sequencing, and gene editing approaches, we propose to address these important open questions by studying the influence UPRmt exerts on the environments of i) mitochondria (including to study the composition and regulation of RNA granules), ii) cytosol (adjustments of translation, metabolism, and proliferation) and iii) neighboring cells (modification by non-cell autonomous signaling). Additionally, we aim to develop an iPSC-based UPRmt model.
On cellular and organismal level, there ought to be mechanisms to signal changes in metabolism and proteostasis to increase robustness in neighboring environments. Studying these effects will be crucial for a better understanding of human disease and carries severe implications: i) the possibility of therapeutic treatment by modulating neighboring compartments or cells and ii) the possibility that diseases inducing the UPRmt could have unknown paracrine and endocrine effects on the organism. This proposal holds the potential to uncover a novel layer of regulation of cellular stress with an extensive influence on our understanding of the UPRmt and disease.
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Host institution

JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN

Address

Theodor W Adorno Platz 1
60323 Frankfurt Am Main

Germany

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 1 437 500

Beneficiaries (1)

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JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN

Germany

EU Contribution

€ 1 437 500

Project information

Grant agreement ID: 803565

Status

Ongoing project

  • Start date

    1 February 2019

  • End date

    31 January 2024

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 437 500

  • EU contribution

    € 1 437 500

Hosted by:

JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN

Germany