Keywords: Mitochondria, Gene Expression, mitochondrial RNA polymerase, post-translational modifications, cancer Internship Duration: 30/11/-1 - 30/11/-1
Head of the hosting team: Inge KÜHL
Website: Click here
Address of the host laboratory: Inge KUHL Team Mammalian Mitochondrial Gene Expression and Function in Health and Disease (MATRIX) CNRS, Dep. Biologie Cellulaire 91198 Gif-sur-Yvette France
Supervisor: Inge KühlE-mail: inge.kuhl@i2bc.paris-saclay.fr Phone: 0169823191
Mitochondrial dysfunction deeply contributes to metabolic and neurodegenerative pathologies, cancer and aging because mitochondria are crucial organelles for the energetic balance and metabolism of all eukaryotic cells. Indeed, mitochondria generate most of the cellular energy via their oxidativephosphorylation (OXPHOS) system, which is under dual genetic control of the nuclear and mitochondrial genomes (mtDNA). Thus, expression and maintenance of the mtDNA is critical for cellular energy homeostasis. Both, transcription and maintenance of the mammalian mtDNA depend on a single-subunit mitochondrial RNA polymerase (POLRMT) that produces the transcripts to express mtDNA-encoded proteins and the RNA primer to initiate mtDNA replication, and is thus of key importance for OXPHOS function. A few factors are proposed to regulate mtDNA expression by interacting with POLRMT to modulate its activity, but the underlying mechanisms are unknown and there is strong evidence that not all POLRMT-interacting proteins have been identified. We have previously generated multi-omics data sets from several mouse models with different types of altered mitochondrial gene expression leading to severe OXPHOS dysfunction. In a multi-omics study we found an POLRMT-interacting factor of yet unknown function called MTPPIF. Here, we will investigate its in vivo molecular role and we have preliminary data supporting an essential role of MTPPIF in mammalian OXPHOS biogenesis,. This M2 project aims at shedding light on the in vivo role of the uncharacterized human MTPPIF protein, in particular, of its biological function in mtDNA expression, and how, through post-translational modifications and interaction with other protein partners in trans, MTPPIF could modulate POLRMT function. This project is not only of fundamental but also clinical importance, since MTPPIF is suggested as as a prognostic marker for kidney cancer, and mutations in POLRMT cause primary mitochondrial disease and POLRMT is an oncogene and a potential therapeutic target to fight cancer and obesity-related disease. We are a young dynamic team, this project will be financed by a young researcher starting grant from the ANR. We are looking for a highly-motivated candidate.
Methods of cell biology, molecular biology, biochemistry and bioenergetics. CRISPR/CAs, (Phospho-) Proteomics and imaging. Mammalian and human cell culture.
Miranda M, Bonekamp NA, Kühl I. Starting the engine of the powerhouse: mitochondrial transcription and beyond. Biological Chemistry. 2022. https://doi.org/10.1515/hsz-2021-0416. Hansen FM, Kremer LS, Karayel O, Larsson N-G, Kühl I, Mann M. Mitochondrial phosphoproteomes are functionally specialized across tissues. Life Sci Alliance. 2023. doi: 10.26508/lsa.202302147. Kühl I, Miranda M, Atanassov I, Kuznetsova I, Hinze Y, Mourier A, Filipovska A, Larsson NG. Transcriptomic and proteomic landscape of mitochondrial dysfunction reveals secondary coenzyme Q deficiency in mammals. eLife. 2017. doi:10.7554/eLife.30952
