Reactome | CLPXP degrades mitochondrial matrix proteins

CLPXP degrades mitochondrial matrix proteins

Stable Identifier

R-HSA-9838289

Type

Reaction [uncertain]

Species

Homo sapiens

Compartment

mitochondrial matrix

ReviewStatus

5/5

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CLPXP degrades mitochondrial matrix proteins

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The CLPXP complex comprises two heptameric rings of the barrel-shaped CLPP protease and two hexameric rings of the AAA+ CLPX ATPase (Kang et al. 2002, 2005). Though isolated CLPP subunits have peptidase activity, they only have significant protease activity when complexed with CLPX (Kang et al. 2005). The CLPX subunit unfolds proteins so they can enter the axial pore of the CLPP protease (reviewed in Baker and Sauer 2012, Liu et al. 2014). The CLPXP complex binds and degrades several mitochondrial matrix proteins (Lee et al. 2021, Key et al. 2021), including ALAS1 bound to heme (Kubota et al. 2016, Nomura et al. 2021). CLPXP can also regulate proteins involved in bioenergetics such as components of the electron transport chain suggesting that it can regulate proteins in the inner mitochondrial membrane (Seo et al. 2016, Ishizawa et al. 2019, Mabanglo et al. 2022). CLPXP is thought to be involved in the mitochondrial unfolded protein response (inferred from C. elegans homologs in Haynes et al. 2007 and mouse homologs in Lian et al. 2023). Peptides produced by CLPXP are transported from the mitochondria into the cytosol and activate ATF5 (ATFS-1 in C. elegans). ATF5 subsequently translocates to the nucleus where it enhances the expression of mitochondrial proteases (CLPP and LONP1) and chaperones (HSP60 and GRP75) to restore proteostasis (inferred from C. elegans homologs in Haynes et al. 2010, inferred from mouse homologs in Deepa et al. 2016, Fiorese et al. 2016, inferred from rat homologs in Lian et al. 2023). Recessive mutations in the CLPP subunit of the CLPXP complex cause Perreault Syndrome, which is characterized by congenital sensorineural loss, ataxia, azoospermia (male infertility), ovarian failure, psychomotor retardation, ataxia, autism and epilepsy (Jenkinson et al. 2013, Demain et al. 2017, Faridi et al. 2022).

Literature References

PubMed ID	Title	Journal	Year
15522782	Crystallography and mutagenesis point to an essential role for the N-terminus of human mitochondrial ClpP Maurizi, MR, Thompson, M, Kang, SG, Mueser, T, Ahvazi, B	J Struct Biol	2004
11923310	Functional proteolytic complexes of the human mitochondrial ATP-dependent protease, hClpXP Singh, SK, Maurizi, MR, Steven, AC, Wang, N, Huang, NN, Ortega, J, Kang, SG	J Biol Chem	2002
34943861	Inactivity of Peptidase ClpP Causes Primary Accumulation of Mitochondrial Disaggregase ClpX with Its Interacting Nucleoid Proteins, and of mtDNA Torres-Odio, S, West, AP, Bach, NC, Shalev, S, Gispert, S, Auburger, G, Reichlmeir, M, Key, J, Freisinger, P, Wittig, I, Prokisch, H, Koepf, G, Sieber, SA, Newman, WG	Cells	2021
22710082	Substrate recognition and processing by a Walker B mutant of the human mitochondrial AAA+ protein CLPX Dougan, DA, Morimoto, RI, Saiyed, T, Truscott, KN, Brötz-Oesterhelt, H, Lowth, BR, Kirstein-Miles, J	J Struct Biol	2012
33637676	LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival Rhee, HW, Park, DH, Chae, YC, Seo, JK, Lee, YJ, Lee, YG, Shin, KJ, Nam, Y, Kim, HW	Oncogenesis	2021
27496948	Novel Mechanisms for Heme-dependent Degradation of ALAS1 Protein as a Component of Negative Feedback Regulation of Heme Biosynthesis Kubota, Y, Furuyama, K, Yamashita, R, Katoh, Y, Nomura, K, Kaneko, K	J Biol Chem	2016
16115876	Human mitochondrial ClpP is a stable heptamer that assembles into a tetradecamer in the presence of ClpX Maurizi, MR, Ginsburg, A, Ortega, J, Kang, SG, Dimitrova, MN	J Biol Chem	2005