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Mitochondrial surveillance activates the primary UPRmt

ABSTRACT: The mitochondrial unfolded protein response (UPRmt) is critical for protecting mitochondria against proteotoxic stress. Current UPRmt models propose that mitochondrial defects are detected by cytosolic surveillance mechanisms after release of damage into the cytosol. However, these findings are based on models that induce rapid and severe mitochondrial dysfunction, and thus their mode of toxicity contrasts sharply from physiologically occurring mitochondrial damage, e.g. the gradual accumulation of reactive oxygen species (ROS) during age-related decline or chronic respiratory chain defects. Here, we employed a chemogenetic strategy that induces low levels of H2O2 in the mitochondrial matrix to investigate cellular responses to physiologically relevant levels of mitochondrial dysfunction. We uncover that this mild oxidative stress activates the UPRmt independently of cytosolic signals revealing a so far concealed primary surveillance mechanism within mitochondria. Moreover, we identify the mitochondrial presequence proteases MPP and Oct1 as early molecular targets of ROS: Oxidative stress induces glutathionylation of critical cysteine residues, resulting in diminished proteolytic activity and the accumulation of proteotoxic precursor aggregates in the matrix. These aggregates are detected by intramitochondrial surveillance systems, activating UPRmt signaling. Our findings uncover the primary response to mitochondrial dysfunction, and highlight the organelle's capacity for self-surveillance and its ability to initiate early and rapid protective signaling in the face of mitochondrial dysfunction.

INSTRUMENT(S):

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Marcin Luzarowski

LAB HEAD: Marcin Luzarowski

PROVIDER: PXD061965 | Pride | 2026-04-07

REPOSITORIES: Pride

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			Action	DRS
	PRIDE_Sample_List.txt	Txt
	Q25070-23-120-06.raw	Raw
	Q25070-23-120-07.raw	Raw
	Q25070-23-120-08.raw	Raw
	Q25070-23-120-09.raw	Raw

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Orphan precursor proteins and ROS activate the mitochondrial UPR_Redox proteomics

Project description:The mitochondrial unfolded protein response (UPRmt) safeguards mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis. How the mitochondrial protein misfolding information is signalled to the nucleus as part of the human UPRmt remains unclear. Here, we showed that UPRmt signalling is carried out by the co-occurrence of two individual signals – ROS production in mitochondria and accumulation of orphan mitochondrial proteins in the cytosol. Combining proteomics and genetic approaches, we identified that mitochondrial protein misfolding caused the release of ROS into the intermembrane space (IMS), which was essential for UPRmt signalling. ROS released from mitochondria oxidized the cytosolic HSP40 protein DNAJA1 to enhance recruitment of cytosolic HSP70 to orphan mitochondrial proteins that accumulated in parallel in the cytosol due to mitochondrial import defect. This recruitment leads to the release of HSF1 from HSP70 and its subsequent translocation to the nucleus to activate transcription of UPRmt related genes. Strikingly, we found that combining ROS and the accumulation of orphan mitochondrial proteins in the cytosol was sufficient and necessary to activate the UPRmt. Our findings reveal that monitoring of ROS and orphan mitochondrial proteins in cytosol allows an elegant surveillance to control the UPRmt via HSF1 activation in human cells. These observations reveal a novel link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling.

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Mitochondrial surveillance activates the primary UPRmt

Project description:The mitochondrial unfolded protein response (UPRmt) is critical for protecting mitochondria against proteotoxic stress. Current UPRmt models propose that mitochondrial defects are detected by cytosolic surveillance mechanisms after release of damage into the cytosol. However, these findings are based on models that induce rapid and severe mitochondrial dysfunction, and thus their mode of toxicity contrasts sharply from physiologically occurring mitochondrial damage, e.g. the gradual accumulation of reactive oxygen species (ROS) during age-related decline or chronic respiratory chain defects. Here, we employed a chemogenetic strategy that induces low levels of H2O2 in the mitochondrial matrix to investigate cellular responses to physiologically relevant levels of mitochondrial dysfunction. We uncover that this mild oxidative stress activates the UPRmt independently of cytosolic signals revealing a so far concealed primary surveillance mechanism within mitochondria. Moreover, we identify the mitochondrial presequence proteases MPP and Oct1 as early molecular targets of ROS: Oxidative stress induces glutathionylation of critical cysteine residues, resulting in diminished proteolytic activity and the accumulation of proteotoxic precursor aggregates in the matrix. These aggregates are detected by intramitochondrial surveillance systems, activating UPRmt signaling. Our findings uncover the primary response to mitochondrial dysfunction, and highlight the organelle's capacity for self-surveillance and its ability to initiate early and rapid protective signaling in the face of mitochondrial dysfunction.

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