Contributions of ubiquitin signaling to the maintenance of mitochondrial import channels
1 PhD project proposal in the IPP summer call Molecular Mechanisms in Genome Stability & Gene Regulation
Scientific Background
Mitochondria are crucial for cellular energy production, metabolism, and balance. The TOM complex facilitates protein import into mitochondria, which is vital for their function. Mitochondria-derived vesicles (MDVs) remove faulty TOM proteins, preserving mitochondrial health. The ubiquitin system, involving E3 ligases like MARCH5 and possibly MUL1/MAPL or PRKN, along with the DUB USP30, regulates this process, though specifics remain unclear. The relevance of this process for human disease is also still unclear.
Our project aims to decipher the ubiquitin code governing MDV-mediated quality control for mitochondrial import channels and its mechanistic implications. Aim 1 involves defining the ubiquitylation response in MDV formation through genetic approaches inducing TOM complex blockage. Aim 2 seeks to understand how ubiquitylation affects MDV formation by identifying functionally relevant ubiquitylation targets and manipulating their modification status. Aim 3 investigates the consequences of defective ubiquitin signaling on mitochondrial shape and function, clarifying its role in mitochondrial proteostasis.
Through cellular physiology measurements, genetic tools, and mutagenesis, we aim to uncover the mechanisms underlying MDV-mediated quality control and its impact on mitochondrial function and morphology. This research will provide insights into maintaining mitochondrial health and potential therapeutic targets for mitochondrial disorders.
PhD project: Contributions of ubiquitin signaling to the maintenance of mitochondrial import channels
The project is a collaborative project with the group of Helle Ulrich at the IMB Mainz and is funded within the DFG priority program Integration of mitochondria into the cellular proteostasis network” (SPP 2453). The priority program brings together 15 tandem groups in Germany with a common interest in the integration of mitochondria into the cellular proteostasis network and organizes meetings, summer schools etc. In tandem with the group of Helle Ulrich at the IMB, the Methnerlab will characterize different models for the induction of mitochondrial protein import clogging including an optogenetic model. We will also establish the visualization and quantification of MDVs in different physiological and also pathophysiological conditions. We will ultimately clarify the contributions of ubiquitin signaling to mitochondrial physiology upon clogging of mitochondrial import channels.
If you are interested in this project, please select Methner as your group preference in the IPP application platform.
Publications relevant to this project
König T, McBride HM. (2024) Mitochondrial-derived vesicles in metabolism, disease, and aging. Cell Metab. Jan 2;36(1):21–35. Link
König T, Nolte H, Aaltonen MJ, Tatsuta T, Krols M, Stroh T, Langer T, McBride HM. (2021) MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control. Nat Cell Biol [Internet]. Dec 6 Link
Renz C, Asimaki E, Meister C, Albanèse V, Petriukov K, Krapoth NC, Wegmann S, Wollscheid HP, Wong RP, Fulzele A, Chen JX, Léon S, Ulrich HD. (2024) Ubiquiton—An inducible, linkage-specific polyubiquitylation tool. Mol Cell. Jan 18;84(2):386–400.e11. Link
Wolf C, Pouya A, Bitar S, Pfeiffer A, Bueno D, Rojas-Charry L, Arndt S, Gomez-Zepeda D, Tenzer S, Bello FD, Vianello C, Ritz S, Schwirz J, Dobrindt K, Peitz M, Hanschmann EM, Mencke P, Boussaad I, Silies M, Brüstle O, Giacomello M, Krüger R, Methner A. (2022) GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton. Commun Biol. Jun 3;5(1):541. Link
Zhang L, Dietsche F, Seitaj B, Rojas-Charry L, Latchman N, Tomar D, Wüst RC, Nickel A, Frauenknecht KB, Schoser B, Schumann S, Schmeisser MJ, Vom Berg J, Buch T, Finger S, Wenzel P, Maack C, Elrod JW, Parys JB, Bultynck G, Methner A. (2022) TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy. Life Sci Alliance. Oct;5(10):e202201478. Link