A06 | The role of mitochondria for cellular protection against ferroptosis
Prof. Dr. Thomas Langer
Max Planck Institute for Biology of Ageing
Contact: langer(at)age.mpg.de
For more information visit: Langer Lab
Abstract
Mitochondria play an active role in cell death control and are emerging as central regulators of innate immunity. In addition to their well-described role in apoptosis, mitochondria have also been linked to other modes of regulated cell death, such as necroptosis, ferroptosis and pyroptosis. This project will examine how the mitochondrial i-AAA protease YME1L regulates cell survival, mtDNA release and inflammatory responses on a molecular level and how this relates to neurodegeneration and tissue-specific cell death in vivo. These studies will help define the role of mitochondria at the interface between cell death and inflammation.
Recent Publications
2026
Flores-Romero H, Pena-Blanco A, Aufdermauer J, Dadsena S, Neubert P, Hohorst L, Cors E, Zollo C, Larrañaga-SanMiguel A, Zaldunbide J, Nenchova M, Carvalho-Schaefer Y, Langer T, Häcker G, Garcia-Saez AJ. MTCH2 promotes BAX and BAK self-assembly and apoptotic pore growth. Nat Struct Mol Biol. 2026 Apr 29. doi: 10.1038/s41594-026-01805-8. Epub ahead of print. PMID: 42056306.
Ndoci M, Bhattacharya S, Agrawal I, Hinze Y, Lemke K, Schumacher AL, Uijttewaal E, Elling U, Lawo S, Giavalisco P, Langer T, Deshwal S. Mitochondria limit coenzyme Q export under cholesterol biosynthetic stress. J Cell Biol. 2026 Aug 3;225(8):e202507174. doi: 10.1083/jcb.202507174. Epub 2026 Jun 8. PMID: 42257675; PMCID: PMC13245278.
Project A06 Publications 2nd Funding Period 2024 - 2027
2025
Kaul H, Isermann L, Senft K, Popovic M, Georgomanolis T, Baumann L, Sivanesan P, Pouikli A, Nolte H, Lucic B, Hildebrandt X, Seidel K, Gnad T, Gaedke F, Göbel U, Peters F, Cherevatenko M, Park JH, Schauss A, Peltzer N, Brüning JC, Kornfeld JW, Pfeifer A, Langer T, Lusic M, Wickström SA, Frezza C, Trifunovic A. 2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction. Nat Metab. 2025 Aug;7(8):1593-1613. doi: 10.1038/s42255-025-01332-8. Epub 2025 Aug 1. PMID: 40750944; PMCID: PMC12373511.
Project A06 Publications 1st Funding Period 2020 - 2023
2023
Grotehans, N., McGarry, L., Nolte, H., Xavier, V., Kroker, M., Narbona-Pérez, Á.J., Deshwal, S., Giavalisco, P., Langer, T. and MacVicar, T. Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression. EMBO J. doi: 10.15252/embj.2022113256.
Deshwal, S., Onishi, M., Tatsuta, T., Bartsch, T., Cors, E., Ried, K., Lemke, L., Nolte, H., Giavalisco, P. & Langer, T. (2023) Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7. Nat Cell Biol (2023). https://doi.org/10.1038/s41556-022-01071-y
2022
Ahola, S., Rivera Mejías, P., Hermans, S., Chandragiri, S., Giavalisco, P., Nolte, H., Langer, T. (2022) OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy. Cell Metabolism Vol 34, Issue 11, 1.11.22 pages 17845-1891.e7 https://doi.org/10.1016/j.cmet.2022.08.017
2021
Willenborg, S., Sanin, D.E., Jais, A., Ding, X.,Ulas, T., Nüchel, J., Popović, M., MacVicar, T., Langer, T., Schultze, J.L., Gerbaulet, A., Roers, A., Pearce, E.J., Brüning, J.C., Trifunovic, A., Eming, S.A. (2021) Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metabolism 33,1–17 December 7, 2021. https://doi.org/10.1016/j.cmet.2021.10.004
Bahat, A., MacVicar, T., and Langer, T. (2021) Metabolism and Innate Immunity Meet at the Mitochondria.
Sprenger, H.G., MacVicar, T., Bahat, A., Fiedler, K.U., Hermans, S., Ehrentraut, D., Ried, K., Milenkovic, D., Bonekamp, N., Larsson, N.G., Nolte, H., Giavalisco, P. & Langer. T. (2021) Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity.Nature Metabolism 26.04.2021 https://doi.org/10.1038/s42255-021-00385-9
Project related Publications
2013 - 2019
Sprenger, H.G., Wani, G., Hesseling, A., König, T., Patron, M., MacVicar, T., Ahola, S., Wai, T., Barth, E., Rugarli, E.I., Bergami, M., and Langer, T. (2019). Loss of the mitochondrial i-AAA protease YME1L leads to ocular dysfunction and spinal axonopathy. EMBO Mol. Med. 11, e9288.
Saita, S., Nolte, H., Fiedler, K.U., Kashkar, H., Venne, A.S., Zahedi, R.P., Krüger, M., and Langer, T. (2017). PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis. Nat Cell Biol 19, 318-328.
Korwitz, A., Merkwirth, C., Richter-Dennerlein, R., Troder, S.E., Sprenger, H.G., Quiros, P.M., Lopez-Otin, C., Rugarli, E.I., and Langer, T. (2016). Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria. J Cell Biol 212, 157-166.
Wai, T., Saita, S., Nolte, H., Müller, S., König, T., Richter-Dennerlein, R., Sprenger, H.G., Madrenas, J., Mühlmeister, M., Brandt, U., Krüber, M., and Langer, T. (2016). The membrane scaffold SLP2 anchors a proteolytic hub in mitochondria containing PARL and the i-AAA protease YME1L. EMBO Rep 17, 1844-1856.
MacVicar, T., and Langer, T. (2016). OPA1 processing in cell death and disease - the long and short of it. J Cell Sci 129, 2297-2306.
Wai, T., Garcia-Prieto, J., Baker, M.J., Merkwirth, C., Benit, P., Rustin, P., Ruperez, F.J., Barbas, C., Ibanez, B.*, and Langer, T.* (2015). Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350, aad0116.* co-senior authorship.
Quiros, P.M., Langer, T., and Lopez-Otin, C. (2015). New roles for mitochondrial proteases in health, ageing and disease. Nat Rev Mol Cell Biol 16, 345-359.
Anand, R., Wai, T., Baker, M.J., Kladt, N., Schauss, A.C., Rugarli, E., and Langer, T. (2014). The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J Cell Biol 204, 919-929.
Baker, M.J., Lampe, P.A., Stojanovski, D., Korwitz, A., Anand, R., Tatsuta, T., and Langer, T. (2014). Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics. EMBO J 33, 578-593.
Potting, C., Tatsuta, T., König, T., Haag, M., Wai, T., Aaltonen, M.J., and Langer, T. (2013). TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid. Cell Metab 18, 287-295.