Reactome | Mitochondrial protein degradation

Mitochondrial protein degradation

Stable Identifier

R-HSA-9837999

DOI

10.3180/R-HSA-9837999.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Mitochondrial proteases participate in proteostasis, the regulation of proteins to maintain a functional proteome, by degrading unfolded, unassembled, and oxidatively damaged proteins (reviewed in Ng et al. 2021, Song et al. 2021). Degradation of mitochondrial proteins by proteases also serves to regulate transcription by TFAM, oxidative phosphorylation by electron carriers, lipid translocation by PRELID1 and STARD7, and mitochondrial fission and fusion by OPA1 and OMA1 (reviewed in Ahola et al. 2019). Because of the bacterial origin of mitochondria, they contain a number of bacterial type proteases, including LONP1 in the matrix, CLPP:CLPX (CLPXP) in the matrix, HTRA2 (OMI) in the intermembrane space, AFG3L2 in the mitochondrial inner membrane and protruding into the matrix, and YME1L1 in the mitochondrial inner membrane and protruding into the intermembrane space (reviewed in Deshwal et al. 2020, Szczepanowska and Trifunovic 2022).
The hexameric LONP1 complex, which is homologous to Lon proteases of eubacteria such as E. coli, binds substrate proteins in the matrix and inner membrane, unfolds them in an ATP-dependent mechanism, and degrades them (reviewed in Gibellini et al. 2020). LONP1 also acts as an ATP-dependent chaperone that is independent of its protease function (reviewed in Gibellini et al. 2020).
Like LONP1, the CLPXP complex unfolds matrix proteins in an ATP-dependent reaction and degrades them, however, the ATPase/unfolding function and the protease function are performed by separate subunits, with CLPX hexamers unfolding substrate proteins and translocating them to CLPP tetradecamers for processive degradation (reviewed in Mabanglo et al. 2021, Mabanglo and Houry 2022).
AFG3L2 (m-AAA+) forms either homohexamers or heterohexamers with its paralog SPG7 (Paraplegin) that are anchored in the mitochondrial inner membrane and protrude into the matrix (reviewed in Patron et al. 2018, Steele and Glynn 2019, Zhang and Mao 2020). The substrate protein enters the central channel formed by the ATPase domains of AFG3L2 and is unfolded and translocated to the pore formed by the protease domains, where it is degraded (reviewed inZhang and Mao 2020).
Like AFG3L2, YME1L1 (YME1L, i-AAA+) is a homohexameric complex that is anchored in the mitochondrial inner membrane, however, YME1L1 protrudes into the intermembrane space where it unfolds substrate proteins of the intermembrane space and inner membrane in an ATP-dependent reaction and then degrades them (reviewed in Steele and Glynn 2019, Ohba et al. 2020, Zhang and Mao 2020).
HTRA2 (OMI) forms soluble trimeric complexes in the intermembrane space that degrade substrate proteins, notably amyloid precursor proteins that are translocated to the intermembrane space and inner membrane. HTRA2 released from mitochondria into the cytosol also participates in regulating apoptosis (reviewed in Vande Walle et al. 2008).
Mutations in mitochondrial proteases cause diseases, such as spastic paraplegia (SPG7), ataxia (AFG3L2), and Parkinson's Disease (HTRA2), that typically have neurological symptoms among others (reviewed in Su et al. 2019, Gomez-Fabra Gala and Vogtle 2021).

Literature References

PubMed ID	Title	Journal	Year
33093673	Quality control of the mitochondrial proteome Song, J, Herrmann, JM, Becker, T	Nat Rev Mol Cell Biol	2021
33453058	Mitochondrial proteases in human diseases Gomez-Fabra Gala, M, Vögtle, FN	FEBS Lett	2021
18174901	The mitochondrial serine protease HtrA2/Omi: an overview Vande Walle, L, Lamkanfi, M, Vandenabeele, P	Cell Death Differ	2008
35245501	Recent structural insights into the mechanism of ClpP protease regulation by AAA+ chaperones and small molecules Mabanglo, MF, Houry, WA	J Biol Chem	2022
32075415	Mitochondrial Proteases: Multifaceted Regulators of Mitochondrial Plasticity Deshwal, S, Fiedler, KU, Langer, T	Annu Rev Biochem	2020
31377246	Mitochondrial AAA proteases: A stairway to degradation Steele, TE, Glynn, SE	Mitochondrion	2019
30205651	Progress in research on the role of Omi/HtrA2 in neurological diseases Su, XJ, Huang, L, Qu, Y, Mu, D	Rev Neurosci	2019
32325699	AAA+ ATPases in Protein Degradation: Structures, Functions and Mechanisms Zhang, S, Mao, Y	Biomolecules	2020
32087062	Regulation of mitochondrial plasticity by the i-AAA protease YME1L Ohba, Y, MacVicar, T, Langer, T	Biol Chem	2020
30670467	Mitochondrial Proteolysis and Metabolic Control Ahola, S, Langer, T, MacVicar, T	Cold Spring Harb Perspect Biol	2019
33662258	Quality control of the mitochondrion Ng, MYW, Wai, T, Simonsen, A	Dev Cell	2021
34446368	Substrates and interactors of the ClpP protease in the mitochondria Mabanglo, MF, Bhandari, V, Houry, WA	Curr Opin Chem Biol	2022
29451229	m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration Patron, M, Sprenger, HG, Langer, T	Cell Res	2018
33971087	Mitochondrial matrix proteases: quality control and beyond Szczepanowska, K, Trifunovic, A	FEBS J	2022
32475470	The biology of Lonp1: More than a mitochondrial protease Gibellini, L, De Gaetano, A, Mandrioli, M, Van Tongeren, E, Bortolotti, CA, Cossarizza, A, Pinti, M	Int Rev Cell Mol Biol	2020