Christian Frezza

Faculty of Medicine, Faculty of Math. Nat. Sciences

Prof. Dr. Christian Frezza

Principal Investigator
Alexander von Humboldt Professor of Metabolomics in Aging
Head of Research Area 2

+49 221 478 84308

christian.frezza[at]uni-koeln.de

Website

FrezzaLab

christian-frezza-a24b0b2

Christian-Frezza

Curriculum Vitae

Research Areas

Metabolomics in Ageing

Our group seeks to understand the contribution of dysregulated metabolism to aging-associated disorders, in particular focusing on cancer caused by mutations in the metabolic enzyme of the TCA cycle Fumarate Hydratase (FH).

Research Focus

Figure 1: Oncogenic signaling in FH-deficient cells

Figure 2: Investigating the mechanisms that underpin tissue-specific tumorigenesis upon FH loss

Deregulation of metabolism is an established hallmark of aging-associated diseases, including cancer. The team of scientists led by Prof. Dr. Frezza tackles new questions at the interface of metabolism, cancer, immunity, and tissue degeneration. There are three main research areas in the Frezza group.

The role of mitochondria in cellular homeostasis in cancer and aging disorders. Loss of the TCA cycle enzyme Fumarate Hydratase (FH) causes Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), characterized by tumours of the skin and uterus and renal cancer. The team aims to understand how FH loss predisposes to cancer in specific tissues, with distinct severity and progression, by investigating the connection of mitochondria dysfunction with cell death signaling, proteome homeostasis, and microenvironmental factors including the immune system response and microbiome interactions.
How the molecular responses to mitochondria dysfunction can contribute to disease initiation, including signaling through the integrated stress response, the inflammation cascade, and the remodeling of chromatin structure and function.
Development of new analytical and computational approaches for the integration of multi-dimensional datasets to investigate the role of metabolism in age-related disorders.

Our Goals

The long-term goal of the group is to understand the critical role of metabolism in cancer and other aging-associated diseases. The team currently focuses on understanding how metabolic transformation driven by mitochondrial dysfunction regulates the process of tissue-specific tumorigenesis. These findings and approaches will then be extended to other models of aging and aging-related diseases, to identify metabolic markers of disease initiation and to establish novel therapeutic strategies and diagnostic tools.

Metabolism is the spark of life. Understanding its regulatory principles is key for elucidating the aetiology of human diseases and how to cure them.

Another goal of the group is to develop novel pipelines for multi-dimensional analysis of experimentally generated datasets. These analysis platforms aim to integrate signaling pathways, metabolic networks, gene regulatory interactions between biomolecules, and generate new computational approaches to model diseases. Finally, a major endeavour of the group is to develop new techniques to analyze cell metabolism at the single-cell level. The team has made fundamental discoveries on how FH loss alters cellular metabolism, causing cancerous transformation in selected tissues, and how cells compensate for the mitochondrial dysfunction to maintain homeostasis.

Key Publications

Sciacovelli M, ..., Frezza C. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature, 2016; 31;537(7621):544-547. doi: 10.1038/nature19353.
Tyrakis PA, Yurkovich EM, Sciacovelli M, Papachristou EK, Bridges HR, Gaude E, Schreiner A, D’Santos C, Hirst J, Hernandez-Fernaud J, Springett R, Griffiths JR, Frezza C. Fumarate Hydratase Loss Causes Combined Respiratory Chain Defects. Cell Reports, 2017; 24;21(4):1036-1047. doi: 10.1016/j.celrep.2017.09.092.
Sciacovelli M, …, Frezza C. Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression. Nat Commun. 2022 Dec 20;13(1):7830. doi: 10.1038/s41467-022-35036-4. PMID: 36539415
Zecchini V, ..., Prudent J^§ & Frezza C^§. Fumarate induces vesicular release of mtDNA to drive innate immunity. Nature, 2023; 615(7952):499-506. doi: 10.1038/s41586-023-05770-w. ^§co-senior authors
Rogerson C, ..., Frezza C. FOXA2 controls the anti-oxidant response in FH-deficient cells. Cell Rep. 2023 Jul 25;42(7):112751. doi: 10.1016/j.celrep.2023.112751.