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.
Highlights
Mitochondria are cellular organelles with a double-membrane structure that perform several crucial functions for the homeostasis of eukaryotic cells
The length of translation time plays an important role in mRNA localization to the mitochondria, and it has been shown that increased translation time due to a translation elongation stall caused by polyproline sequences is one way exploited by yeast cell to extend the “competent state” of a translating mRNA to be recruited to the mitochondrion; other mechanisms that increase translation duration such as increased ORF length, the presence of rare codons within the transcript, and mRNA structures could likely play a similar role in mRNA localization [67]
The modulation of gene expression has been traditionally attributed to transcription regulation, in the last few years it has become increasingly evident that many processes were regulated at translational level [198], and among those, assembly and activity of respiratory complexes, whose subunits are inserted into the nascent macromolecular units in a co-translational manner [75]
Summary
Mitochondria are cellular organelles with a double-membrane structure that perform several crucial functions for the homeostasis of eukaryotic cells. Their main role is to generate chemical energy through the oxidative phosphorylation (OXPHOS) system, which is composed of five multi-subunit respiratory complexes associated to the inner mitochondrial membrane (IMM). Accurate assembly of respiratory complexes requires a tight coordination between cytosolic and mitochondrial translation and efficient protein quality control (PQC) mechanisms to monitor protein import and turnover [8, 9]. We describe the importance of mitochondrial protein quality control systems in coordinating these translational programs, and present the case of the molecular chaperone TRAP1, likely first example of a protein with dual localization that participate in the regulation of proteostasis on both sides of the mitochondrial membranes. We provide some hints about dysfunctions of mitochondrial protein homeostasis and cancer development, highlighting the most relevant therapeutic approaches proposed so far in the field
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