Rescuing mitochondria in peril under oxidative stress

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• Professor Kostas Tokatlidis | University of Glasgow
• Wednesday 23 November 2022, 15:00-16:00
• MRC MBU, Level 7 Lecture Theatre, The Keith Peters Building, CB2 0XY.

If you have a question about this talk, please contact hkb33.

Mitochondria need to have defence mechanisms to respond to deleterious stresses like oxidative stress that can damage proteins, DNA and lipids. Cellular H2O2 homeostasis and signalling in S. cerevisiae are mediated by a specific H2O2 -inducible transcriptional response engaging the YAP1 transcription factor. Activation of YAP1 in the cytosol depends on the thiol peroxidase Gpx3/Orp1. We have found that, upon H2O2 stress, Gpx3 activates another, YAP1 -independent and compartment-specific defence pathway in mitochondria. This is initiated by a stress-dependent mitochondrial targeting of Gpx3 guided by an N-terminal targeting peptide that is appended to the protein by alternative translation in the cytosol. This extended form of Gpx3 follows a novel import pathway that is independent of outer membrane import receptors, ATP hydrolysis or the inner membrane potential and can still operate in dysfunctional mitochondria with a damaged inner membrane. Gpx3 in the IMS engages in both protein-protein and protein-lipid interactions facilitating optimal operation of the oxidative folding MIA machinery and protecting the inner mitochondrial membrane from oxidative damage. We have found that, under stress conditions, Gpx3 allows mitochondria to bypass the disulfide relay mechanism that is thought until now to be essential for the function of Mia40. This stress-induced bypass rescues the biogenesis process in the mitochondrial IMS , which would otherwise be blocked. The molecular interactions underpinning this new pathway are important for optimal mitochondrial quality control, proteostasis and cell survival.

This talk is part of the MRC Mitochondrial Biology Unit Seminars series.

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• MRC MBU, Level 7 Lecture Theatre, The Keith Peters Building, CB2 0XY
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