Abstract

Mitochondria are sites of complex and adaptive gene expression regulation, responding to metabolic changes to fine-tune cellular function. Their ability to generate energy through oxidative phosphorylation relies on precise RNA processing, including mitochondrial RNA (mtRNA) maturation, modification, and mitoribosome assembly. These processes require close coordination between nuclear and mitochondrial gene expression, allowing mitochondria to adapt to environmental signals without the need for changes in transcription.

Our project explores a novel layer of mitochondrial RNA regulation: ADP ribosylation, a recently discovered NAD+-derived RNA modification. We propose that this modification acts as a metabolic sensor, linking mitochondrial function and gene expresstion to cellular energy status. Since mitochondria have high NAD+ levels and contain key regulatory enzymes, ADP ribosylation may serve as a crucial switch in mtRNA metabolism. In addition, we aim to uncover how specific RNA-binding proteins (RBPs) influence mitochondrial activity by regulating the expression of critical factors. We will discover critical RBPs involved in mitochondrial responses in stem cell differentiation and aging using genetically encoded metabolite sensors combined with CRISPR screens targeting RBPs. This research will provide new insights into how mitochondria integrate metabolic signals post-transcriptionally.

Project-related publications

Huppertz I, Perez-Perri JI, Mantas P, Sekaran T, Schwarzl T, Russo F, Ferring-Appel D, Koskova Z, Dimitrova-Paternoga L, Kafkia E, Hennig J, Neveu PA, Patil K, Hentze MW (2022) Riboregulation of Enolase 1 activity controls glycolysis and embryonic stem cell differentiation. Mol Cell. Jul 21;82(14):2666-2680.e11. DOI: 10.1016/j.molcel.2022.05.019. Epub 2022 Jun 15. PMID: 35709751.

Perez-Perri JI, Ferring-Appel D, Huppertz I, Schwarzl T, Sahadevan S, Stein F, Rettel M, Galy B, Hentze MW. The RNA-binding protein landscapes differ between mammalian organs and cultured cells. Nat Commun. Apr 12;14(1):2074. DOI: 10.1038/s41467-023-37494-w. PMID: 37045843