Aleksandra Trifunovic

Institute of Mitochondrial Disease and Ageing

Mitochondrial Signalling

Mitochondria not only are hosts for numerous essential metabolic pathways, like energy production, they have also been a central signaling hub which regulates processes crucial in determining cell fate particularly under stressful conditions.

Research Focus

The primary focus of our research is to unravel the precise signaling cascade of pathogenic mechanisms leading to mitochondrial diseases and aging. Our ultimate goal is to identify new therapeutic targets and strategies to address these conditions.

When mitochondria experience stress or dysfunction, they communicate by sending signals to the cell nucleus, triggering various adaptive responses. Activated transcription factors stimulate the expression of specific gene sets, facilitating the cell's adaptation to these changes. Recent scientific breakthroughs highlight that mitochondria not only serve as a signaling platform but also act as active producers of potent damage-associated molecular patterns (DAMPs), controlling the activation of innate immunity and inflammatory responses. Our research aims to delve deeper into these largely unknown mechanisms, crucial in determining the extent of tissue-specific defects arising from respiratory deficiency, systemic metabolic alterations, and inflammatory changes.

Our group has successfully advanced research approaches focusing on the intricate communication between mitochondria and other cellular components. We have challenged the current understanding by demonstrating that mitochondrial dysfunction can be sensed independently of respiratory chain deficiency, questioning established views on the molecular mechanisms contributing to mitochondrial disease development. Moreover, we have reported variations in the induction of mitochondrial stress response pathways between C. elegans and mice. Our quest extends to identifying novel pathways involved in cellular and organismic adaptation to mitochondrial dysfunction, with potential implications for lifespan prolongation and the discovery of new homeostatic pathways.

Our research primarily centers on unraveling the intricate signaling cascade underlying pathogenic mechanisms that contribute to mitochondrial diseases and aging. The ultimate objective is to pinpoint novel therapeutic targets and devise potential treatment strategies.

Our Goals

  • We aim to unravel the intricate regulation of mitochondrial biogenesis under stress conditions, where cells respond to heightened energy demands by engaging in a complex process that coordinates nuclear and mtDNA gene expression. Despite its significance, the regulatory mechanisms governing this process remain poorly understood. Our research brings attention to the depletion of cytoplasmic ribosomal proteins, a critical pathway that promotes mitochondrial gene expression. The SPTF-3 transcription factor emerges as a major regulator in this context, leading to inefficient ribosomal biogenesis and impacting translation fidelity. Our primary objective is to uncover how nutrient deprivation and stress influence cytoplasmic translation fidelity, resulting in increased mitochondrial OXPHOS biosynthesis.
  • In a parallel effort centered on understanding the role of mitochondria in modulating innate immunity, our project focuses on the mitochondrial matrix protease CLPP, a key component of quality control machinery. Preliminary data suggest that CLPP prevents the release of mitochondrial DAMPs and the activation of the IFN-I response. The observation of CLPP deficiency hints at an unexplored crosstalk between innate immunity responses and systemic metabolism control. Employing cell and in vivo models, our goal is to unravel molecular mechanisms, map mitochondrial DAMPs, and decipher signaling cascades. This research significantly contributes to our understanding of inflammatory, autoimmune, ischemic heart disease, and cancer conditions.
  • Furthermore, our exploration extends to the regulatory role of intramitochondrial proteases in the stress responses of mitochondria. Challenging prior notions, we emphasize that macrodegradation processes like mitophagy do not solely regulate OXPHOS remodeling and turnover. Instead, we investigate a salvage pathway, specifically safeguarding against dysfunctional CI accumulation. Our overarching objective is to delve into the proteolytic control of OXPHOS function by mitochondrial matrix proteases CLPP and LONP1 under both physiological and pathophysiological conditions. This research aims to contribute to a nuanced understanding of how these proteases shape the metabolic status of cells.

Key Publications

  1. Kaspar S, Oertlin C, Szczepanowska K, Kukat A, Senft K, Lucas C, Brodesser S, Hatzoglou M, Larsson O, Topisirovic I, Trifunovic A. (2021)  "Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR." Sci Adv. 2021 May 26;7(22):eabf0971
  2. Croon M, Szczepanowska K, Popovic M, Lienkamp C, Senft K, Brandscheid CP, Bock T, Gnatzy-Feik L, Ashurov A, Acton RJ, Kaul H, Pujol C, Rosenkranz S, Krüger M, Trifunovic A. (2022), FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction. Sci Adv. 2022 Apr 8;8(14):eabn7105
  3. Szczepanowska K, Senft K, Heidler J, Herholz M, Kukat A, Höhne MN, Hofsetz E, Becker C, Kaspar S, Giese H, Zwicker K, Guerrero-Castillo S, Baumann L, Kauppila J, Rumyantseva A, Müller S, Frese CK, Brandt U, Riemer J, Wittig I, Trifunovic A (2020). “A salvage pathway maintains highly functional respiratory complex I”. Nat Commun. 2020 Apr 2;11(1).
  4. Hermeling JC, Herholz M, Baumann L, Cores EC, Zečić A, Hoppe T, Riemer J, Trifunovic A. (2022), Mitochondria-originated redox signalling regulates KLF-1 to promote longevity in Caenorhabditis elegans. Redox Biol. 2022 Nov 19;58:102533. doi: 10.1016/j.redox.2022.102533. Epub ahead of print. PMID: 36442394.
  5. Herholz, M., E. Cepeda, L. Baumann, A. Kukat, J. Hermeling, S. Maciej, K. Szczepanowska, V. Pavlenko, P. Frommolt and A. Trifunovic (2019). "KLF-1 orchestrates a xenobiotic detoxification program essential for longevity of mitochondrial mutants." Nat Commun 10(1): 3323