Mitochondrial ribosomes in cancer

Abstract

Mitochondria play fundamental roles in the regulation of life and death of eukaryotic cells. They mediate aerobic energy conversion through the oxidative phosphorylation (OXPHOS) system, and harbor and control the intrinsic pathway of apoptosis. As a descendant of a bacterial endosymbiont, mitochondria retain a vestige of their original genome (mtDNA), and its corresponding full gene expression machinery. Proteins encoded in the mtDNA, all components of the multimeric OXPHOS enzymes, are synthesized in specialized mitochondrial ribosomes (mitoribosomes). Mitoribosomes are therefore essential in the regulation of cellular respiration. Additionally, an increasing body of literature has been reporting an alternative role for several mitochondrial ribosomal proteins as apoptosis-inducing factors. No surprisingly, the expression of genes encoding for mitoribosomal proteins, mitoribosome assembly factors and mitochondrial translation factors is modified in numerous cancers, a trait that has been linked to tumorigenesis and metastasis. In this article, we will review the current knowledge regarding the dual function of mitoribosome components in protein synthesis and apoptosis and their association with cancer susceptibility and development. We will also highlight recent developments in targeting mitochondrial ribosomes for the treatment of cancer.

Keywords: Apoptosis; Cancer; Mitochondrial ribosomes; Therapy.

Figure 1. Structure of mitochondrial ribosomes

Cryo-EM structures of human 28S mt-SSU and 37S mt-LSU (PDB 3J9M). Individual proteins relevant to apoptosis and cancer, which are mentioned in the text, are depicted in different colors and labeled.

Figure 2. Involvement of mitoribosome subunit mS29/DAP3 in activating the extrinsic and intrinsic pathways of apoptosis

The schematic portraits the components and major events of the extrinsic and mitochondrial apoptotic pathways. The extrinsic pathway or the death receptor pathway is activated by the binding of death receptors to their ligands such as FASL (FAS ligand), TNFa, (tumor necrosis factor) or TRAIL (TNF-related apoptosis-inducing ligand). This promotes the recruitment of adaptor proteins such as FAS-associated death domain protein (FADD) that bind to death effector domain containing caspase −8 or −10. Formation of this complex results in dimerization and activation of caspase −8 that can induce two different pathways to apoptosis; the first one is the direct cleavage and activation of executioner caspases −3, −6 or −7. The other one is the cleavage and activation of the BH3-interacting domain death agonist (BID), the truncated product of which is tBID. tBID leads to the interaction of BCL-2-associated X protein (BAX) and BCL-2 antagonist or killer (BAK) and induction mitochondrial outer membrane permeability (MOMP), thereby generating a crosstalk between the extrinsic and intrinsic apoptotic pathways. The intrinsic or mitochondrial pathway is initiated by different apoptotic stimuli or environmental stresses such as DNA damage, ROS, endoplasmic reticulum (ER) stress, irradiation, which activate B-cell lymphoma 2 (BCL-2) homology 3 (BH3)-only proteins leading to translocation of BAX and BAK to mitochondria and induction of MOMP. Anti-apoptotic BCL-2 proteins prevent MOMP by binding to BH3-only proteins, tBID and activated BAX or BAK. MOMP induces the release of cytochrome c from the mitochondrial intermembrane space (IMS) to the cytosol that promotes caspase activation and apoptosis. Cytochrome c binds to the apoptotic protease-activating factor 1 (APAF1) and promotes the formation of the apoptosome that subsequently recruits and activates the initiator caspase, caspase 9. Caspase 9 further cleaves and activates executioner caspases −3, −6 or −7 leading to apoptotic cell death. Other proapoptotic proteins that are released following MOMP are second mitochondria-derived activator of caspase (SMAC; also known as DIABLO) and OMI (also known as HTRA2) that interacts with the X-linked inhibitor of apoptosis protein (XIAP) to prevent its inhibitory function on caspase −9 and −3. mS29 (death-associated protein 3, DAP3) is depicted in the figure as an example of one of the three mitoribosomal subunits involved in apoptosis. mS29/DAP3 is predicted to regulate mitochondrial translation and apoptosis in various ways. mS29/DAP3 mediate contact with intersubunit bridges thereby assisting in monosomes formation and mito translation. mS29/DAP3 is also involved in mitochondrial dynamics by regulating the phosphorylation of DRP1 (dynamin-related GTPase involved in mitochondrial fission). In addition, mS29/DAP3 can initiate the extrinsic apoptotic pathway through its interactions with ligands of death receptors such as FASL, TRAIL and TNFα. mS29/DAP3 also co-localizes with FADD and participates in the formation of Death-Inducing Signaling Complex (DISC), which exists in the cell in an inactive form by the action of protein kinase B (AKT/PKB). DAP3 also interacts with FADD through the involvement of interferon-β promoter stimulator 1 (IPS1), which is a caspase activation and recruitment domain (CARD) bearing protein, present in the mitochondrial outer membrane. This complex further recruits procaspase-8, thereby triggering further downstream cleavage and activation of caspase resulting in cell death. mS29/DAP3 induces mitochondria-mediated apoptosis through the activation of p38 MAPK and the JNK signaling pathway. Two other pro-apoptotic mitoribosome LSU proteins, mL41/BMRP that interacts with 16S rRNA and associates with mL65/PDCD9, have been also being depicted in the schematic. However, their pro-apoptotic mechanism/s of action remain to be unveiled.