Reactome | Mitochondrial unfolded protein response (UPRmt)

Mitochondrial unfolded protein response (UPRmt)

Stable Identifier

R-HSA-9841251

Type

Pathway

Species

Homo sapiens

ReviewStatus

3/5

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Mitochondrial unfolded protein response (UPRmt)

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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).

Literature References

PubMed ID	Title	Journal	Year
12198143	A mitochondrial specific stress response in mammalian cells Zhao, Q, Wang, J, Levichkin, IV, Ryan, MT, Hoogenraad, NJ, Stasinopoulos, S	EMBO J	2002
28566324	Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals Williams, RW, D'Amico, D, Auwerx, J, Gygi, SP, Finley, D, Quirós, PM, Zamboni, N, Prado, MA	J Cell Biol	2017
38136659	Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases Sánchez-Alcázar, JA, Munuera-Cabeza, M, Romero-Domínguez, JM, López-Cabrera, A, Álvarez-Córdoba, M, Piñero-Pérez, R, Romero-González, A, Gómez-Fernández, D, Suárez-Carrillo, A, Talaverón-Rey, M, Reche-López, D, Cilleros-Holgado, P	Biomolecules	2023
35908669	The mitochondrial unfolded protein response: A multitasking giant in the fight against human diseases Tan, K, Zong, R, Zhou, Z, Fan, Y	Ageing Res Rev	2022
27350246	Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation Münch, C, Harper, JW	Nature	2016
28470001	mtDNA, Metastasis, and the Mitochondrial Unfolded Protein Response (UPR^mt) Germain, D, Kenny, TC	Front Cell Dev Biol	2017
27426517	The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR Rosin, N, Haynes, CM, Schulz, AM, Fiorese, CJ, Pellegrino, MW, Lin, YF	Curr Biol	2016
37286597	A cytosolic surveillance mechanism activates the mitochondrial UPR Tascher, G, Gößner, I, Münch, C, Sutandy, FXR	Nature	2023
17849004	Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements Aldridge, JE, Hoogenraad, NJ, Horibe, T	PLoS One	2007
28799020	From discovery of the CHOP axis and targeting ClpP to the identification of additional axes of the UPRmt driven by the estrogen receptor and SIRT3 Germain, D, Kenny, TC	J Bioenerg Biomembr	2017
19652361	Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice Rajamohan, SB, Gupta, MP, Isbatan, A, Gupta, M, Sundaresan, NR, Kim, G	J. Clin. Invest.	2009
21486948	Estrogen receptor mediates a distinct mitochondrial unfolded protein response Papa, L, Germain, D	J Cell Sci	2011
30049264	The different axes of the mammalian mitochondrial unfolded protein response Münch, C	BMC Biol	2018
29165426	The mitochondrial UPR: mechanisms, physiological functions and implications in ageing Haynes, CM, Shpilka, T	Nat Rev Mol Cell Biol	2018
11139588	Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance Patel, NM, Nakshatri, H, Ali, S, Campbell, RA, Constantinidou, D, Bhat-Nakshatri, P	J Biol Chem	2001
24324009	SirT3 regulates the mitochondrial unfolded protein response Papa, L, Germain, D	Mol Cell Biol	2014