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The Mitochondrial Unfolded Protein Response

The Mitochondrial Unfolded Protein Response

Objective

Mitochondria—organelles specialized in energy harvesting through oxidative phosphorylation (Oxphos)—critically influence metabolism, health and lifespan. Evolved from endosymbiotic proteobacteria, mitochondria retained the vestige of the bacterial genome, the mitochondrial DNA, which encodes 13 subunits of the Oxphos complexes, while the remaining ~80 Oxphos components and the rest of the mitochondrial proteome are encoded on nuclear DNA, translated in the cytoplasm and imported in the mitochondria. The control of the mitochondrial proteome by two genomes exposes these organelles to proteotoxic stress in case of an imbalance between the nuclear- and mitochondrial-encoded proteins. Upon such stress, several mitochondrial protein quality control (mtPQC) pathways, including the mitochondrial unfolded protein response (UPRmt), will sense, transmit and re-establish mitochondrial proteostasis through mitonuclear regulatory circuits. Although a robust UPRmt circuit improves health and lifespan in C. elegans, much less is known about mtPQC in vertebrates. We propose here to characterize UPRmt pathways across 3 species by: (1) mapping mammalian UPRmt genes and networks in vivo after the induction of the UPRmt in a large murine genetic reference population at 3 different times throughout life with 2 different inducers; (2) integrating these UPRmt networks with a wide set of clinical, mitochondrial, and molecular phenotypes collected throughout life to establish links between UPRmt mechanisms and health- and lifespan; (3) mechanistically validating the most important UPRmt pathways, using loss-of-function studies in cells, worms and mice; and (4) clinically translating promising UPRmt hits, using genetic association studies in human cohorts. The insight gained will mechanistically define the UPRmt networks from worms to humans and will provide the next step in translating the benefits of activating the UPRmt—initially observed in invertebrates—into targeted human therapies.
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Host institution

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE

Address

Batiment Ce 3316 Station 1
1015 Lausanne

Switzerland

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 2 500 000

Beneficiaries (1)

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ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE

Switzerland

EU Contribution

€ 2 500 000

Project information

Grant agreement ID: 787702

Status

Ongoing project

  • Start date

    1 November 2018

  • End date

    31 October 2023

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 2 500 000

  • EU contribution

    € 2 500 000

Hosted by:

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE

Switzerland