Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins
- Rosario Avolio1,7,
- Ilenia Agliarulo2,7,
- Daniela Criscuolo1,
- Daniela Sarnataro1,
- Margherita Auriemma1,
- Sabrina De Lella1,
- Sara Pennacchio1,
- Giovanni Calice3,
- Martin Y. Ng4,
- Carlotta Giorgi5,
- Paolo Pinton5,
- Barry S. Cooperman4,
- Matteo Landriscina2,6,
- Franca Esposito1 and
- Danilo Swann Matassa1
- 1Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy;
- 2Institute of Experimental Endocrinology and Oncology “G. Salvatore”–IEOS, National Research Council of Italy (CNR), Naples 80131, Italy;
- 3Laboratory of Preclinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture 85028, Italy;
- 4Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA;
- 5Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy;
- 6Department Medical and Surgical Science, University of Foggia, Foggia 71122, Italy
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↵7 These authors contributed equally to this work.
Abstract
A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein, we identify the molecular mechanisms involved, showing that TRAP1 (1) binds both mitochondrial and cytosolic ribosomes, as well as translation elongation factors; (2) slows down translation elongation rate; and (3) favors localized translation in the proximity of mitochondria. We also provide evidence that TRAP1 is coexpressed in human tissues with the mitochondrial translational machinery, which is responsible for the synthesis of respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, strongly suggesting the existence of a tight feedback loop between protein synthesis and energy metabolism, based on the demonstration that a single molecular chaperone plays a role in both mitochondrial and cytosolic translation, as well as in mitochondrial respiration.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.277755.123.
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Freely available online through the Genome Research Open Access option.
- Received January 31, 2023.
- Accepted July 19, 2023.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
