Mitochondrial protein degradation

Stable Identifier
R-HSA-9837999
DOI
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

Becker, T, Song, J, Herrmann, JM

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

Lamkanfi, M, Vandenabeele, P, Vande Walle, L

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

Glynn, SE, Steele, TE

Mitochondrion 2019
30205651 Progress in research on the role of Omi/HtrA2 in neurological diseases

Su, XJ, Huang, L, Mu, D, Qu, Y

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, Langer, T, MacVicar, 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

Simonsen, A, Ng, MYW, Wai, T

Dev Cell 2021
34446368 Substrates and interactors of the ClpP protease in the mitochondria

Mabanglo, MF, Houry, WA, Bhandari, V

Curr Opin Chem Biol 2022
29451229 m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration

Sprenger, HG, Langer, T, Patron, M

Cell Res 2018
33971087 Mitochondrial matrix proteases: quality control and beyond

Trifunovic, A, Szczepanowska, K

FEBS J 2022
32475470 The biology of Lonp1: More than a mitochondrial protease

Bortolotti, CA, Van Tongeren, E, De Gaetano, A, Mandrioli, M, Gibellini, L, Cossarizza, A, Pinti, M

Int Rev Cell Mol Biol 2020
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