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MRC Mitochondrial Biology Unit


Professor Giovanna Mallucci

Founding Principal Investigator, Altos Labs Cambridge Institute of Science, Cambridge UK

"ER stress and mitochondria"

Widespread repression of protein synthesis rates is a key feature of Endoplasmic Reticulum (ER) stress, mediated by the ER sensor kinase PERK. This is a major mechanism of neuronal death in neurodegenerative disease and a target for therapy. This talk will cover an overview of ER stress in neurodegeneration and its modulation and also focus on new data focusing on the subcellular modulation of PERK activation.  Thus, during ER stress, while select transcripts escape this repression, global translational down-regulation impacts crucial protein levels in all cellular compartments, beyond the ER. How the cell manages this paradox is unclear. PERK has a unique cytoplasmic loop within its kinase domain that binds PERK’s target, eIF2α. We identified the mitochondrial protein, ATAD3A, as a new interactor of the loop, binding to a highly conserved region within it. During ER stress, increased interaction between ATAD3A and PERK attenuates PERK signalling to eIF2α, removing the translational block on several mitochondrial proteins. This occurs at novel context-dependent, mitochondria-ER contact sites. The interaction provides a previously unknown mechanism for fine-tuning translational repression at a local level, mitigating the impact of ER stress on mitochondria. Further, it represents a new target for selective modulation of PERK-eIF2α signalling in diseases from cancer to neurodegeneration.

Wednesday, 1 March, 2023 - 15:00
Event location: 
MRC MBU, Level 7 Lecture Theatre, The Keith Peters Building, CB2 0XY