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Mitochondrial unfolded protein response (UPRmt)

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-9841251

PubChem

R-HSA-9841251

Description

Misfolded proteins in mitochondria activate the mitochondrial unfolded protein response (mtUPR), a program of gene expression that increases capacities for protein folding and protein degradation within the mitochondria (Zhao et al. 2002, Aldridge et al. 2007, reviewed in Cilleros-Holgado et al. 2023). Four interrelated pathways that regulate the mtUPR have been delineated: activation of Heat Shock Factor 1 (HSF1) by dissociation from HSPA1A,B (HSP70) (Sutandy et al. 2023), enhanced translocation of ATF5 to the nucleus (Fiorese et al. 2016), activation of the estrogen receptor alpha (ESR1) by phosphorylation, and activation of FOXO3 by deacetylation (reviewed in Kenny and Germain 2017, Munch 2018, Shpilka and Haynes 2018, Zhou et al. 2022).
The mtUPR appears to be initiated by the accumulation of reactive oxygen species (ROS) and mitochondrial precursor proteins in the cytosol (Sutandy et al. 2023). The ROS oxidize cysteine residues on DNAJA1, causing DNAJA1 to displace HSF1 from the chaperone HSPA1A,B (HSP70). HSF1 then transits to the nucleus, trimerizes, and activates expression of genes encoding chaperones (Sutandy et al. 2023).
The transcription factor ATF5, which is normally imported into mitochondria, instead accumulates in the cytosol and transits to the nucleus (Fiorese et al. 2016), where it acts with HSF1 to increase expression of chaperone genes (Fiorese et al. 2016, Sutandy et al. 2023). ATF5 may act downstream of HSF1, as ATF5 is not required to initiate the mtUPR (Sutandy et al. 2023).
ROS also activate the protein kinase AKT1 (PKB) (Papa and Germain 2011), which phosphorylates the estrogen receptor ESR1 (Campbell et al. 2001, Papa and Germain 2011). Phosphorylated ESR1 transits to the nucleus and, independently of estrogen, activates the expression of HTRA2 (OMI), NRF1, and other genes involved in mitochondrial homeostasis as part of the mitochondrial unfolded response (Papa and Germain 2011).
Through an uncharacterized mechanism, ROS cause increased expression of the deacetylase SIRT3, which directly or indirectly causes the deacetylation of the transcription factor FOXO3. Deacetylated FOXO3 in the nucleus increases expression of the antioxidant enzymes mitochondrial superoxide dismutase (SOD2, MnSOD) and peroxisomal catalase (CAT) in the mitochondrial unfolded response (Papa and Germain 2014).
Though ATF4 and CHOP are also key regulators of the mtUPR (Zhao et al. 2002, Quiros et al. 2017), the mechanisms that activate them in response to unfolded protein are not well characterized and may involve the phosphorylation of the EIF2S1 subunit of the translation factor eIF2alpha; however, none of the four known EIF2S1 kinases (GCN2, HRI, PERK, and PKR) are required for activation of CHOP (Munch and Harper 2016).

Click on a node on the pathway to see its details. Glycoproteins are marked with a glycoprotein icon in their name.

SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

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UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
O43524	Forkhead box protein O3	FKHRL1 FOXO3 FOXO3A	view
P03372	Estrogen receptor	ESR ESR1 NR3A1	view
P04040	Catalase	CAT	view
P04179	Superoxide dismutase [Mn], mitochondrial	SOD2	view
P0DMV8	Heat shock 70 kDa protein 1A	HSP72 HSPA1 HSPA1A HSPA1B HSX70	view
P0DMV9	Heat shock 70 kDa protein 1B	HSP72 HSPA1 HSPA1A HSPA1B HSX70	view
P10809	60 kDa heat shock protein, mitochondrial	HSP60 HSPD1	view
P31749	RAC-alpha serine/threonine-protein kinase	AKT1 PKB RAC	view
P36776	Lon protease homolog, mitochondrial	LONP1 PRSS15	view
P38646	Stress-70 protein, mitochondrial	GRP75 HSPA9 HSPA9B mt-HSP70	view

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