Mitochondrial protein degradation

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).