Trifunovic, Aleksandra - B 11

Role of mitochondria in the regulation of innate immunity responses

Prof. Dr. Aleksandra Trifunovic
Prof. Dr. Aleksandra Trifunovic

Institute for Mitochondrial Diseases and Ageing | CECAD Research Center

CMMC - PI - B 11

Institute for Mitochondrial Diseases and Ageing | CECAD Research Center

Joseph-Stelzmann-Str. 26

50931 Cologne

Introduction

Due to its bacterial origin mitochondria contain numerous potent immunostimulatory damage associated molecular patterns (DAMPs), including hypomethylated mtDNA, dsRNA and formylated proteins, that can activate the innate immune system, type I interferon (IFN-I) in particular. The exposure of cells to mtDNA has long been known to be immunostimulatory and the release of mtDNA into the cytosol can activate a number of pattern recognition receptors (PPRs) to trigger a variety of innate immune responses. 

In recent years it was increasingly recognized that beside supporting the antiviral response orchestrated by PRRs, mtDNA release in the cytoplasm or extracellular space can also cause chronic inflammation contributing to the growing list of disease pathologies ranging from primary mitochondrial disease to various autoimmune diseases (arthritis, Lupus and ALS) or age-associated neurodegenerative disease. While growing facts in recent studies have expanded the role of mitochondria in the modulation of innate immunity, we are still left with more questions than answers and this project proposal aims to answer some of them. 

Our preliminary data suggest that mtDNA release, outside of cell death processes, might be a highly regulated process that does not depend on the level of mitochondrial dysfunction or physical damage. Instead, we show that parts of mitochondrial quality control machinery guard against release of mitochondrial DAMPs and the activation of IFN-I response. Using a combination of cell and in vivo models we aim to discover molecular mechanisms behind these processes. 

Clinical Relevance

Recent scientific advances reveal that mitochondria play a central role in proinflammatory signalling, on one side as a signalling platform, but also as an active producer of potent DAMPs that control activation of innate immunity and the inflammatory response. Thus, mitochondrial dysfunctions have been related to severe chronic inflammatory disorders, and also neurodegenerative, liver and heart disease. 

However, very little is known about molecular mechanisms that govern these seemingly highly regulated processes. Strategies aimed at re-establishing normal mitochondrial physiology could represent both preventive and therapeutic interventions for various pathologies related to exacerbated inflammation.

Lab Website

For more information about Prof. Trifunovic's research and work, please visit Trifunovic Lab.

2024 (up to June)
  • Moschandrea C, Kondylis V, Evangelakos I, Herholz M, Schneider F, Schmidt C, Yang M, Ehret S, Heine M, Jaeckstein MY, Szczepanowska K, Schwarzer R, Baumann L, Bock T, Nikitopoulou E, Brodesser S, Kruger M, Frezza C, Heeren J, Trifunovic A, and Pasparakis M (2024). Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes. Nature625, 385-392. doi:10.1038/s41586-023-06857-0.
2023
  • Montoro-Gamez C, Nolte H, Molinie T, Evangelista G, Troder SE, Barth E, Popovic M, Trifunovic A, Zevnik B, Langer T, and Rugarli EI (2023). SARM1 deletion delays cerebellar but not spinal cord degeneration in an enhanced mouse model of SPG7 deficiency. Brain 146, 4117-4131. doi:10.1093/brain/awad136.
     
  • Peker E, Weiss K, Song J, Zarges C, Gerlich S, Boehm V, Trifunovic A, Langer T, Gehring NH, Becker T, and Riemer J (2023). A two-step mitochondrial import pathway couples the disulfide relay with matrix complex I biogenesis. J Cell Biol 222. doi:10.1083/jcb.202210019.
     
  • Rozsivalova DH, Popovic M, Kaul H, and Trifunovic A (2023). Isolation of Functional Mitochondria and Pure mtDNA from Murine Tissues. Methods Mol Biol 2615, 3-16. doi:10.1007/978-1-0716-2922-2_1.
     
  • Spath MR, Hoyer-Allo KJR, Seufert L, Hohne M, Lucas C, Bock T, Isermann L, Brodesser S, Lackmann JW, Kiefer K, Koehler FC, Bohl K, Ignarski M, Schiller P, Johnsen M, Kubacki T, Grundmann F, Benzing T, Trifunovic A, Kruger M, Schermer B, Burst V, and Muller RU (2023). Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway. J Am Soc Nephrol 34, 772-792. doi:10.1681/ASN.0000000000000087.