Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins

Author:

Avolio RosarioORCID,Agliarulo IleniaORCID,Criscuolo DanielaORCID,Sarnataro DanielaORCID,Auriemma Margherita,De Lella Sabrina,Pennacchio Sara,Calice Giovanni,Ng Martin Y.,Giorgi Carlotta,Pinton PaoloORCID,Cooperman Barry S.,Landriscina MatteoORCID,Esposito FrancaORCID,Matassa Danilo SwannORCID

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.

Funder

Sviluppo di Approcci Terapeutici INnovativi per patologie neoplastiche resistenti ai trattamenti [SATIN]

National Institutes of Health

Lega Italiana per la Lotta contro I Tumori

Finanziamento della Ricerca in Ateneo

Publisher

Cold Spring Harbor Laboratory

Subject

Genetics (clinical),Genetics

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