Reactome | LONP1 degrades mitochondrial matrix proteins

LONP1 degrades mitochondrial matrix proteins

Stable Identifier

R-HSA-9838081

Type

Reaction [uncertain]

Species

Homo sapiens

Compartment

mitochondrial matrix

ReviewStatus

5/5

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LONP1 degrades mitochondrial matrix proteins

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ATP hydrolysis drives translocation of the substrate protein to the active site of LONP1 (Ambro et al. 2014, Mohammed et al. 2022) where it induces the active conformation of LONP1 (Shin et al. 2021). LONP1 predominantly cleaves peptide bonds adjacent to hydrophobic amino acid residues (He et al. 2018). LONP1 degrades several mitochondrial matrix proteins (Lee et al. 2021), including steroidogenic acute regulatory protein (STAR) (Ondrovicova et al. 2005), the helicase TWNK (Twinkle, PEO1) (Kunova et al. 2017), oxidized aconitase (ACO2) (Bota and Davies 2002), HMGCS2 (Bai et al. 2023), and unassembled ribosomal subunits (Kunova et al. 2017). Phosphorylation of the HMG1 domain of TFAM prevents DNA binding and LONP1 specifically degrades TFAM that is not bound to DNA (Lu et al. 2013). LONP1 in association with mtHSP70 also possesses an ATP-dependent chaperone (protein folding) activity that is independent of its protease activity (Shin et al. 2021, Matsushima et al. 2021). A dominant mutation in LONP1 (c.901C>T; p.R301W) causes excessive protease activity and reduced chaperone activity that results in reduced mitochondrial function and encephalopathy (Besse et al. 2020). Mutations in LONP1 cause cerebral, ocular, dental, auricular, and skeletal anomalies (CODAS) syndrome (MIM 600373) (Dikoglu et al. 2015, Strauss et al. 2015).

Literature References

PubMed ID	Title	Journal	Year
36629048	LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease Bai, M, Wu, M, Jiang, M, He, J, Deng, X, Xu, S, Fan, J, Miao, M, Wang, T, Li, Y, Yu, X, Wang, L, Zhang, Y, Huang, S, Yang, L, Jia, Z, Zhang, A	EMBO Mol Med	2023
24520911	Mutations to a glycine loop in the catalytic site of human Lon changes its protease, peptidase and ATPase activities Ambro, Ľ, Pevala, V, Ondrovičová, G, Bellová, J, Kunová, N, Kutejova, E, Bauer, J	FEBS J	2014
28377575	The role of Lon-mediated proteolysis in the dynamics of mitochondrial nucleic acid-protein complexes Kunová, N, Ondrovičová, G, Bauer, JA, Bellová, J, Ambro, Ľ, Martináková, L, Kotrasová, V, Kutejova, E, Pevala, V	Sci Rep	2017
30120231	Multiple domains of bacterial and human Lon proteases define substrate selectivity He, L, Luo, D, Yang, F, Li, C, Zhang, X, Deng, H, Zhang, JR	Emerg Microbes Infect	2018
12198491	Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism Bota, DA, Davies, KJ	Nat Cell Biol	2002
33637676	LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival Lee, YG, Kim, HW, Nam, Y, Shin, KJ, Lee, YJ, Park, DH, Rhee, HW, Seo, JK, Chae, YC	Oncogenesis	2021
23201127	Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease Lu, B, Lee, J, Nie, X, Li, M, Morozov, YI, Venkatesh, S, Bogenhagen, DF, Temiakov, D, Suzuki, CK	Mol Cell	2013
15870080	Cleavage site selection within a folded substrate by the ATP-dependent lon protease Ondrovicová, G, Liu, T, Singh, K, Tian, B, Li, H, Gakh, O, Perecko, D, Janata, J, Granot, Z, Orly, J, Kutejova, E, Suzuki, CK	J Biol Chem	2005
35870450	Catalytic cycling of human mitochondrial Lon protease Mohammed, I, Schmitz, KA, Schenck, N, Balasopoulos, D, Topitsch, A, Maier, T, Abrahams, JP	Structure	2022