Mitochondrial ATP-Dependent Proteases—Biological Function and Potential Anti-Cancer Targets

Abstract

Cells must eliminate excess or damaged proteins to maintain protein homeostasis. To ensure protein homeostasis in the cytoplasm, cells rely on the ubiquitin-proteasome system and autophagy. In the mitochondria, protein homeostasis is regulated by mitochondria proteases, including four core ATP-dependent proteases, m-AAA, i-AAA, LonP, and ClpXP, located in the mitochondrial membrane and matrix. This review will discuss the function of mitochondrial proteases, with a focus on ClpXP as a novel therapeutic target for the treatment of malignancy. ClpXP maintains the integrity of the mitochondrial respiratory chain and regulates metabolism by degrading damaged and misfolded mitochondrial proteins. Inhibiting ClpXP genetically or chemically impairs oxidative phosphorylation and is toxic to malignant cells with high ClpXP expression. Likewise, hyperactivating the protease leads to increased degradation of ClpXP substrates and kills cancer cells. Thus, targeting ClpXP through inhibition or hyperactivation may be novel approaches for patients with malignancy.

Autophagy‐independent mitochondrial quality control: Mechanisms and disease associations

“…36 In both the intermembrane space (IMS) and matrix, oxidized or unfolded proteins are cleaned up by mitochondrial proteases. 3,[48][49][50] In IMS, protein degradation is mainly handled by the protease HtrA2/Omi, as well as two other members of the AAA family: m-AAA and i-AAA. 49 The i-AAA protease in yeast and human mitochondria is composed of homohexamers of Yeast Mitochondrial Escape 1 (Yme1) and YME1L, respectively.…”

“…In both the intermembrane space (IMS) and matrix, oxidized or unfolded proteins are cleaned up by mitochondrial proteases 3,48–50 . In IMS, protein degradation is mainly handled by the protease HtrA2/Omi, as well as two other members of the AAA family: m‐AAA and i‐AAA 49 .…”

Feasibility and safety of targeting mitochondria for cancer therapy – preclinical characterization of gamitrinib, a first-in-class, mitochondriaL-targeted small molecule Hsp90 inhibitor

“…Although targeting chaperone-directed proteostasis in mitochondria shows promising antitumor activity, 25 , 26 pharmacologically, this pathway escapes inhibition by small-molecule Hsp90 antagonists with geldanamycin (GA) or non-GA backbones 27 as these agents fail to accumulate in mitochondria. 28 To overcome this conundrum, we generated Gamitrinib ( GA mit ochondrial ma tri x in h ib itor), a first-in-class, mitochondrial-targeted inhibitor of organelle protein folding 25 that links the GA Hsp90 inhibitor 17-allylamino-geldanamyicn (17-AAG, Tanespimycin) 27 to an efficient mitochondrial-import carrier, triphenylphosphonium (TPP).…”

Targeting mitochondrial proteases for therapy of acute myeloid leukaemia

“…So far, varied mitochondrial proteases have been identified in different mitochondrial compartments (Quirós et al, 2015). The functions of these proteases have not been fully elucidated; some of which are only now emerging as prospective therapeutic targets for haematological malignancies (Castelli et al, 2019; Culp‐Hill et al, 2021; Feng et al, 2021; Gomez‐Fabra Gala & Vögtle, 2021). This article provides a comprehensive account of these mitochondrial proteases which may serve as therapeutic targets in haematological tumours, especially in AML.…”