Failure to Guard: Mitochondrial Protein Quality Control in Cancer

Abstract

Mitochondria are energetic and dynamic organelles with a crucial role in bioenergetics, metabolism, and signaling. Mitochondrial proteins, encoded by both nuclear and mitochondrial DNA, must be properly regulated to ensure proteostasis. Mitochondrial protein quality control (MPQC) serves as a critical surveillance system, employing different pathways and regulators as cellular guardians to ensure mitochondrial protein quality and quantity. In this review, we describe key pathways and players in MPQC, such as mitochondrial protein translocation-associated degradation, mitochondrial stress responses, chaperones, and proteases, and how they work together to safeguard mitochondrial health and integrity. Deregulated MPQC leads to proteotoxicity and dysfunctional mitochondria, which contributes to numerous human diseases, including cancer. We discuss how alterations in MPQC components are linked to tumorigenesis, whether they act as drivers, suppressors, or both. Finally, we summarize recent advances that seek to target these alterations for the development of anti-cancer drugs.

Keywords: MPQC; cancer; chaperone; mitochondria; oncogene; protease; proteostasis; therapeutic targeting; tumor suppressor; tumorigenesis.

Figure 1

Proteins are imported into mitochondria through multiple pathways. In yeast, protein precursors are synthesized by ribosomes in the cytosol and guided to the TOM complex on the OMM by chaperone Hsp70 and Hsp90, with the help of co-chaperones Ydj1 and Sti1. In the presequence pathway (left), precursors are first recognized by Tom20 of the TOM complex in the cytosol. Then, precursors are handed to Tom22 and subsequently brought through the Tom40 channel into the IMS. They are received by Tim50 of the TIM23 complex on the IMM and passed through to the matrix, with the help of the Tim44 protein and mtHsp70. The PAM complex prevents precursors from moving backwards out of the TIM23 complex. MPP cleaves the MTS to release proteins. Icp55 and Oct1 help remove any unstable amino acids from the N-terminal cleavage site of the proteins. Then, the presequence is degraded by PREP, and Oxa1 helps integrate mature proteins into the IMM when needed. In the pathways for non-cleavable proteins (right), carrier proteins (blue), proteins with cysteine residues (red), α-helical (purple), and β-barrel (brown) are shown. Carrier proteins pass through the TOM complex via the Tom40 channel into the IMS. Then, they are carried to their final location in the IMM by the TIM22 complex and other IMS chaperones. Precursors with cysteine residues also pass through the TOM complex via the Tom40 channel. Then, they are received by Mia40, which is regulated by Erv1, and helps create the disulfide bonds between cysteine residues and form mature proteins. α-helical precursors rely on Tom70 for recognition and do not localize to the IMS, as they are integrated into the OMM by the MIM complex. β-barrel precursors pass through the Tom40 pore into the IMS, and then moved to the SAM complex on the OMM via Tim chaperones, including Tim9, Tim10, and Tim12. Then, the SAM complex incorporates the mature proteins into the OMM. TOM: translocase of the outer membrane; OMM: Outer mitochondrial membrane; Hsp70: Heat-shock protein 70; Hsp90: Heat-shock protein 90; Ydj1: Yeast dnaJ 1; Sti1: Stress inducible protein 1; IMS: Intermembrane space; TIM: translocase of the inner membrane; IMM: Inner mitochondrial membrane; PAM: Presequence translocase-associated motor; MPP: Mitochondrial processing peptidase; MTS: Mitochondrial targeting sequence; Icp55: Intermediate cleaving peptidase 55; Oct1: Octapeptidyl aminopeptidase; PREP: Presequence peptidase; Oxa1: Mitochondrial inner membrane protein OXA1; Mia40: Mitochondrial intermembrane space import and assembly protein 40; Erv1: FAD-linked sulfhydryl oxidase ERV1; MIM: mitochondrial import complex; SAM: Sorting and assembly machinery.

Figure 2

Multiple MPQC pathways surveil protein synthesis, import, folding, assembly, and degradation. The MPQC surveillance system can be divided into four pathways based on studies from yeast and humans: 1. Translocation-associated protein degradation. Under standard culture conditions of yeast, Ubx2 recruits Cdc48 to the TOM complex to target prematurely folded, misfolded, or clogged proteins for proteasome-mediated degradation. Under stress conditions, the cytosolic protein Cis1 links Msp1 to Tom70, enabling Msp1 to extract the target proteins from the TOM complex for degradation. When proteins are stalled at ribosomes, Rqc2 adds CAT-tails to the stalled proteins and facilitates their ubiquitylation by Ltn1. Vms1 removes stalled proteins for degradation through preventing Rqc2 to add CAT-tails. 2. Chaperones and proteases: Chaperones and proteases are important for protein transport, folding, and degradation. Chaperones, such as Hsp70, bind to the newly synthesized proteins and prevent their folding before transporting into mitochondria. Upon transportation into the matrix, MTS is cleaved off by MPP, with mtHsp70 working with Hsp60 to further fold the protein into its functional state. m-AAA and i-AAA are located on the OMM to remove damaged proteins under stress. In the matrix, the proteases, Lon and Plpxp, regulate protein turnover and remove damaged proteins that are accumulated under stress. 3. Mitochondrial stress responses: In humans, the i-AAA protein OMA1 cleaves DELE1 into multiple DELE1s, which interact with HRI to phosphorylate eIF2α. The eIF2α-p further regulates gene expression, such as ATF4, ATF5, and CHOP, the upregulation of which further enables the coping of the stress response. 4. Mitophagy and MDVs: When mitochondrial dysfunction persists and proteostasis cannot be restored, the accumulation of dysfunctional polypeptides together with misfolded and unfolded proteins imposes a severe burden onto mitochondria. Under such conditions, PINK1 phosphorylates Parkin, which ubiquitinates the OMM for mitophagy. MDVs serve as another strategy to remove aberrant mitochondrial proteins without losing the whole organelle. TOM: translocase of the outer membrane; TIM: translocase of the inner membrane; UPS: ubiquitin-proteasome degradation system; MDVs: mitochondria-derived vesicles; PINK1: phosphatase and tensin homolog (PTEN)-induced kinase; Parkin: an E3 ubiquitin-protein ligase encoded by PARK2; i-AAA: inner membrane-embedded AAA protease; m-AAA: matrix-embedded AAA protease; MPP: matrix processing peptidase; OMA1: overlapping activity with m-AAA protease; Lon: Lon protease; Clpx: ATP-dependent Clp protease proteolytic subunit X; Clpp: ATP-dependent Clp protease proteolytic subunit P; Ubx2: UBX domain-containing protein 2; Rqc2: ribosome quality control complex subunit 2; Ltn1: E3 Ubiquitin Ligase Listerin; Cdc48: Cell division control protein 48; Cis1: citrinin sensitive knockout protein 1; ATF4: Activating Transcription Factor 4; ATF5: Activating Transcription Factor 5; CHOP: C/EBP homologous protein.