Targeting Mitochondrial Protein Expression as a Future Approach for Cancer Therapy

Abstract

Extensive metabolic remodeling is a fundamental feature of cancer cells. Although early reports attributed such remodeling to a loss of mitochondrial functions, it is now clear that mitochondria play central roles in cancer development and progression, from energy production to synthesis of macromolecules, from redox modulation to regulation of cell death. Biosynthetic pathways are also heavily affected by the metabolic rewiring, with protein synthesis dysregulation at the hearth of cellular transformation. Accumulating evidence in multiple organisms shows that the metabolic functions of mitochondria are tightly connected to protein synthesis, being assembly and activity of respiratory complexes highly dependent on de novo synthesis of their components. In turn, protein synthesis within the organelle is tightly connected with the cytosolic process. This implies an entire network of interactions and fine-tuned regulations that build up a completely under-estimated level of complexity. We are now only preliminarily beginning to reconstitute such regulatory level in human cells, and to perceive its role in diseases. Indeed, disruption or alterations of these connections trigger conditions of proteotoxic and energetic stress that could be potentially exploited for therapeutic purposes. In this review, we summarize the available literature on the coordinated regulation of mitochondrial and cytosolic mRNA translation, and their effects on the integrity of the mitochondrial proteome and functions. Finally, we highlight the potential held by this topic for future research directions and for the development of innovative therapeutic approaches.

Keywords: inter-organelle coordinated translation regulation; mitochondrial protein import; mitochondrial protein quality control (mtPQC); mitochondrial translation; protein synthesis.

Figure 1

The mtDNA is organized in structures called “nucleoids”, in which both core and peripheral proteins contribute to organization, stability and communication of the mtDNA with additional factors. Among the nucleoid components, POLRMT plays a key role, being responsible for the transcription process. Subsequently, the original polycistronic transcript is subject to extensive maturation, yielding mitochondrial tRNAs, rRNAs and mRNAs. The latter encode 13 polypeptides, all members of the respiratory chain, can be stabilized and regulated by RNA-binding proteins such as LRPPRC, SLIRP FASTKD1, and finally translated by inner membrane-tethered mitoribosomes, to be cotranslationally assembled into the OXPHOS complexes. I, II, III, IV: respiratory complexes I-IV.

Figure 2

The nuclear-encoded mitochondrial proteins are synthesized by cytosolic ribosomes (ribo) that can be localized at the OMM, allowing co-translational import of nascent proteins into the organelle via the TOM/TIM complexes. Translating ribosomes can act as a platform for early PQC by ribosome-associated chaperones, including TRAP1, that, under stress conditions, prevents aberrant aggregation of proteins, directing them to co-translational ubiquitin-mediated proteasomal degradation. The imported proteins taking part to respiratory complexes are then assembled in supercomplexes along with the 13 components that are synthesized within the organelle by the mitochondrial ribosomes (mt-ribo). The co-translational insertion of these subunits into the IMM is mediated by OXA1, which is crucial for the assembly of functional respiratory complexes. The same molecular chaperone assisting PQC of mitochondrial proteins, TRAP1, is contemporary a regulator of respiration, through a direct binding to complex II, and an indirect regulation on complex IV, through the stabilization of the inactive form of c-Src, which is known to stimulate complex IV activity. Inhibition of TRAP1 leads to a mtUPR and related stress response. I, II, III, IV: respiratory complexes I-IV.

Figure 3

The mitochondrial proteome is controlled at several levels. The vast majority of mitochondrial proteins is encoded by the nuclear genome; therefore, the transcribed mRNAs must be exported from the nucleus (1) to be translated into the cytosol. This translation process can be compartmentalized through a localization of transcript to the organelle (2) with the contribution of the protein synthesis machinery. Proteins synthesized on the surface of mitochondria can be imported via TOM/TIM (3a) or discarded and degraded if they don’t pass the PQC step (3b). mRNA translation (4) and associated PQC (5) also occur in the mitochondrial matrix. All these steps can be potentially targeted with compound listed in Table 1 and represented here in red.