bims-mitran 2023-07-30 papers

Issue of 2023‒07‒30
three papers selected by
Andreas Kohler

J Transl Med. 2023 Jul 28. 21(1): 512

RNA binding protein: coordinated expression between the nuclear and mitochondrial genomes in tumors.

Jiaoyan Ma, Liankun Sun, Weinan Gao, Yang Li, Delu Dong.

Mitochondria are the only organelles regulated by two genomes. The coordinated translation of nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), which together co-encode the subunits of the oxidative phosphorylation (OXPHOS) complex, is critical for determining the metabolic plasticity of tumor cells. RNA-binding protein (RBP) is a post-transcriptional regulatory factor that plays a pivotal role in determining the fate of mRNA. RBP rapidly and effectively reshapes the mitochondrial proteome in response to intracellular and extracellular stressors, mediating the cytoplasmic and mitochondrial translation balance to adjust mitochondrial respiratory capacity and provide energy for tumor cells to adapt to different environmental pressures and growth needs. This review highlights the ability of RBPs to use liquid-liquid phase separation (LLPS) as a platform for translation regulation, integrating nuclear-mitochondrial positive and retrograde signals to coordinate cross-department translation, reshape mitochondrial energy metabolism, and promote the development and survival of tumor cells.

Keywords: Cytoplasmic translation; LLPS; Mitochondrial translation; OXPHOS; Retrograde signals

DOI: https://doi.org/10.1186/s12967-023-04373-3

Genome Res. 2023 Jul 24. pii: gr.277755.123. [Epub ahead of print]

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

Rosario Avolio, Ilenia Agliarulo, Daniela Criscuolo, Daniela Sarnataro, Margherita Auriemma, Sabrina De Lella, Sara Pennacchio, Giovanni Calice, Martin Y Ng, Carlotta Giorgi, Paolo Pinton, Barry Cooperman, Matteo Landriscina, Franca Esposito, Danilo Swann Matassa.

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, demonstrating that TRAP1: i) binds both mitochondrial and cytosolic ribosomes as well as translation elongation factors, ii) slows down translation elongation rate, and iii) 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.

DOI: https://doi.org/10.1101/gr.277755.123

bioRxiv. 2023 Jul 15. pii: 2023.05.24.542018. [Epub ahead of print]

Structure of mitoribosome reveals mechanism of mRNA binding, tRNA interactions with L1 stalk, roles of cofactors and rRNA modifications.

Vivek Singh, Yuzuru Itoh, Samuel Del'Olio, Asem Hassan, Andreas Naschberger, Rasmus Kock Flygaard, Yuko Nobe, Keiichi Izumikawa, Shintaro Aibara, Juni Andréll, Paul C Whitford, Antoni Barrientos, Masato Taoka, Alexey Amunts.

The mitoribosome translates mitochondrial mRNAs and regulates energy conversion that is a signature of aerobic life forms. We present a 2.2 Å resolution structure of human mitoribosome together with validated mitoribosomal RNA (rRNA) modifications, including aminoacylated CP-tRNA Val . The structure shows how mitoribosomal proteins stabilise binding of mRNA and tRNA helping to align it in the decoding center, whereas the GDP-bound mS29 stabilizes intersubunit communication. Comparison between different states, with respect to tRNA position, allowed to characterize a non-canonical L1 stalk, and molecular dynamics simulations revealed how it facilitates tRNA transition in a way that does not require interactions with rRNA. We also report functionally important polyamines that are depleted when cells are subjected to an antibiotic treatment. The structural, biochemical, and computational data illuminate the principal functional components of the translation mechanism in mitochondria and provide the most complete description so far of the structure and function of the human mitoribosome.

DOI: https://doi.org/10.1101/2023.05.24.542018