Prof. Dr. Christian Frezza

Alexander von Humboldt Professor of Metabolomics in Aging, Faculty of Medicine

Prof. Dr. Christian Frezza CECAD

Prof. Dr. Christian Frezza

Principal Investigator

+49 221 478 84308


Metabolomics in aging

Room: 4.068

CECAD Research Center
Joseph-Stelzmann-Str. 26

50931 Köln

Prof. Dr. Frezza’s group seeks to understand the contribution of dysregulated metabolism to aging-associated disorders, in particular focusing on cancer. A part of the lab investigates how the loss of the mitochondrial enzyme and tumour suppressor Fumarate Hydratase causes renal cancer. Our work has multiple implications: (1) it will provide a mechanistic understanding of the role of metabolism and small molecule metabolites in human diseases; (2) it will generate experimental and computation tools to identify metabolic vulnerabilities that we can use as pharmacological targets for cancer therapy; (3) it will apply metabolomics and multi-omics analyses to mouse and human models to identify metabolic markers of disease initiation for clinical application in early detection and for patient stratification.

Our research: 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. 1) 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. 2) 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. 3) 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 successes: 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. The group showed that fumarate, a metabolite accumulated upon FH loss, drives an epithelial-to-mesenchymal transition (EMT) via the epigenetic suppression of a family of anti-metastatic miRNA, unraveling a new layer of communication between mitochondria and the nucleus based on epigenetic control, and how small molecule metabolites accumulated in the disease state can control cell behavior.

The team also enabled the identification of metabolic rewiring underlying ischemia and reperfusion injury, demonstrating that lack of oxygen leads to the selective accumulation of succinate, which in turn is responsible for the generation of reactive oxygen species during re-oxygenation, contributing to a new understanding of mitochondrial metabolism in conditions of inadequate oxygenation, including organ transplant and stroke.

In the field of immunology, Prof. Frezza’s team contributed to the seminal discovery that two mitochondrial metabolites, succinate and itaconate, play critical roles in shaping macrophage biology, opening up new research in immuno-metabolism.

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. 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.

Our methods/techniques: Prof. Frezza’s laboratory uses genetically modified mouse models and a combination of cell biology, molecular biology, and biochemistry techniques to study the role of altered mitochondrial dysfunction and metabolism in human diseases. A primary analytical tool of the group is metabolomics, which enables the parallel quantification of hundreds of small molecule metabolites. The team also uses computational approaches to integrate datasets from multi-dimensional analyses, including metabolomics, proteomics, and transcriptomics, with the aim to model aging-related disorders and to generate mechanistic hypotheses that will be cross validated experimentally.


Figure 1: Oncogenic signaling in FH-deficient cells

Upon FH loss, cells engage in a complex metabolic reprogramming that is required for survival and growth. We observed a switch in carbon utilization by the TCA cycle: Glucose entry is restricted in FH-deficient cells by inactivation of the pyruvate dehydrogenase, whilst glutamine becomes the major carbon source for TCA cycle metabolites. To divert glutamine-derived carbons in the TCA cycle, cells exploit the haem biosynthesis and degradation pathway, secreting bilirubin. In addition, the loss of FH causes the accumulation of high millimolar levels of fumarate, which is at least partially buffered by the uptake of exogenous arginine via the reversal of the urea cycle enzyme argininosuccinate lyase, and by glutathione, which binds to fumarate forming succinic-glutathione. In the nucleus, fumarate accumulation induces a profound epigenetic reprogramming due to the inhibition of both DNA and histone demethylases (TETs and KDMs respectively). In particular, the inhibition of the demethylation of miR200 was shown to trigger an epithelial-to-mesenchymal transition (EMT) in FH-deficient cells. Fumarate can also activate the transcription factor NRF2 by covalently binding to its negative regulator Keap1 through a modification called succination. Crucially, the inhibition of some of these compensatory pathways can be lethal for FH-deficient cells and has been proposed as anticancer therapy.

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

We hypothesize that tumorigenesis in HLRCC occurs via a two-step mechanism. First, following the loss of FH, only cells in tissues with sufficient metabolic flexibility survive. Second, in these surviving cells, FH loss and the ensuing fumarate accumulation drive phenotypic changes that lead to transformation. The mechanisms underlying tissue-specific permissiveness and the oncogenic events triggered by FH loss can be pharmacologically exploited to prevent cancer cell survival and growth.