Chun-Yu Fu

University of Cologne

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Günter Schwarz

University of Cologne

Katrin Bohl

University Hospital Cologne

Jan‐Wilm Lackmann

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Adam Antebi

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Volker Burst

University of Cologne

Thomas Benzing

University of Cologne

Claas Gloistein

University Hospital Cologne

Felix C. Koehler

University Hospital Cologne

Bernhard Schermer

Centrum für Integrierte Onkologie

Thomas Osterholt

University Hospital Cologne

Cooperative Institutions

Evanston Hospital

University of Cologne

University Hospital Cologne

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

University of Illinois Chicago

Centrum für Integrierte Onkologie

New York University

University of Arizona

Jichi Medical University

Jichi Medical University Saitama Medical Center

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Sulfite oxidase deficiency causes persulfidation loss and H₂S release

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Chun-Yu Fu Joshua B. Kohl Filip Liebsch Davide D’Andrea Max Mai

Abstract Sulfite oxidase (SOX) deficiency is a rare inborn error of cysteine metabolism resulting in severe neurological damage. In patients, sulfite accumulates to toxic levels causing a raise in downstream products S -sulfocysteine (SSC), mediating excitotoxicity, and thiosulfate, a catabolic intermediate/product of H 2 S metabolism. Here, we report a full-body knock-out mouse model for SOX deficiency (SOXD) with a severely impaired phenotype. Amongst the urinary biomarkers, thiosulfate showed a 45-fold accumulation in SOXD mice representing the major excreted S-metabolite. Consistently, we found increased plasma H 2 S, which was derived from sulfite-induced release from persulfides as demonstrated in vitro and in vivo . Mass spectrometric analysis of total protein persulfidome identified a major loss of persulfidation in 20% of the proteome affecting enzymes in amino acids and fatty acid metabolism. Urinary amino acid profiles indicate metabolic rewiring suggesting partial reversal of the TCA cycle thus identifying a novel contribution of H 2 S metabolism and persulfidation in SOXD.

Sulfite oxidase

Catabolism

Metabolome

Sulfur Metabolism

10.1101/2024.03.13.584820

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Citations (1)

Molybdenum Cofactor Deficiency in Humans

Molecules (2022)

Lena Johannes Chun-Yu Fu Günter Schwarz

Molybdenum cofactor (Moco) deficiency (MoCD) is characterized by neonatal-onset myoclonic epileptic encephalopathy and dystonia with cerebral MRI changes similar to hypoxic–ischemic lesions. The molecular cause of the disease is the loss of sulfite oxidase (SOX) activity, one of four Moco-dependent enzymes in men. Accumulating toxic sulfite causes a secondary increase of metabolites such as S-sulfocysteine and thiosulfate as well as a decrease in cysteine and its oxidized form, cystine. Moco is synthesized by a three-step biosynthetic pathway that involves the gene products of MOCS1, MOCS2, MOCS3, and GPHN. Depending on which synthetic step is impaired, MoCD is classified as type A, B, or C. This distinction is relevant for patient management because the metabolic block in MoCD type A can be circumvented by administering cyclic pyranopterin monophosphate (cPMP). Substitution therapy with cPMP is highly effective in reducing sulfite toxicity and restoring biochemical homeostasis, while the clinical outcome critically depends on the degree of brain injury prior to the start of treatment. In the absence of a specific treatment for MoCD type B/C and SOX deficiency, we summarize recent progress in our understanding of the underlying metabolic changes in cysteine homeostasis and propose novel therapeutic interventions to circumvent those pathological changes.

Molybdenum Cofactor

10.3390/molecules27206896

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Sodium thiosulfate, a source of hydrogen sulfide, stimulates endothelial cell proliferation and neovascularization

Frontiers in Cardiovascular Medicine (2022)

Diane Macabrey Jaroslava Joniová Quentin Gasser Clémence Bechelli Alban Longchamp

Therapies to accelerate vascular repair are currently lacking. Pre-clinical studies suggest that hydrogen sulfide (H2S), an endogenous gasotransmitter, promotes angiogenesis. Here, we hypothesized that sodium thiosulfate (STS), a clinically relevant source of H2S, would stimulate angiogenesis and vascular repair. STS stimulated neovascularization in WT and LDLR receptor knockout mice following hindlimb ischemia as evidenced by increased leg perfusion assessed by laser Doppler imaging, and capillary density in the gastrocnemius muscle. STS also promoted VEGF-dependent angiogenesis in matrigel plugs in vivo and in the chorioallantoic membrane of chick embryos. In vitro, STS and NaHS stimulated human umbilical vein endothelial cell (HUVEC) migration and proliferation. Seahorse experiments further revealed that STS inhibited mitochondrial respiration and promoted glycolysis in HUVEC. The effect of STS on migration and proliferation was glycolysis-dependent. STS probably acts through metabolic reprogramming of endothelial cells toward a more proliferative glycolytic state. These findings may hold broad clinical implications for patients suffering from vascular occlusive diseases.

Matrigel

Chorioallantoic membrane

Sodium hydrosulfide

10.3389/fcvm.2022.965965

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Citations (11)

Cysteine Catabolism Is a Central Player in Diet-Induced Renal Stress-Resistance

Journal of the American Society of Nephrology (2021)

Felix C. Koehler Chun-Yu Fu Martin R. Späth Karla Johanna Ruth Hoyer-Allo Katrin Bohl

Catabolism

10.1681/asn.20213210s124b

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Imipramine-mediated Suppression of EGFR Signaling Attenuates Invasive and Progressive Abilities of Hepatocellular Carcinoma Cells

Anticancer Research (2024)

Chun-Yu Fu PEN-AN LIAO TZU-HSIANG LIN Fei‐Ting Hsu Dai-Cheng Dong

Background/Aim: Hepatocellular carcinoma (HCC) is a primary liver cancer with high mortality rates worldwide, necessitating effective therapeutic strategies. Imipramine demonstrates the potential to augment standard treatments of different cancers, highlighting its therapeutic promise in oncology. This study aimed to investigate the potential regulation of imipramine on HCC. Materials and Methods: Cytotoxicity, apoptosis, metastasis, anti-apoptosis and signaling regulation were assessed in Huh7 and Hep3B cells using MTT assay, flow cytometry, and western blotting. Results: Imipramine markedly induced cytotoxicity and Annexin-V activation in Huh7 and Hep3B cells in a time and dose-dependent manner. Mechanistically, imipramine induced cytotoxicity and apoptosis in HCC cells via both extrinsic (Fas-Fas-L) and intrinsic (mitochondrial) apoptosis pathways. It also suppressed HCC metastasis and inhibited epidermal growth factor receptor (EGFR)/mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinases (ERKs) signaling. Conclusion: Imipramine shows promise in enhancing HCC treatment outcomes in patients and targets the EGFR/MEK/ERK signaling pathway in in vitro HCC models, thereby augmenting the effectiveness of standard therapies.

10.21873/anticanres.17360

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Contents

Translational research (2022)

Akinori Aomatsu Shohei Kaneko Katsunori Yanai Hiroki Ishii Kiyonori Ito

10.1016/s1931-5244(22)00080-9

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A systematic analysis of diet-induced nephroprotection reveals overlapping and conserved changes in cysteine catabolism

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Felix C. Koehler Chun-Yu Fu Martin R. Späth Karla Johanna Ruth Hoyer-Allo Katrin Bohl

Abstract Caloric Restriction (CR) extends lifespan and augments cellular stress-resistance from yeast to primates, making CR an attractive strategy for organ protection in the clinic. Translation of CR to patients is complex, due to problems regarding adherence, feasibility and safety concerns in frail patients. Novel tailored dietary regimens, which modulate the dietary composition of macro- and micronutrients rather than reducing calorie intake promise similar protective effects and increased translatability. However, a direct head-to-head comparison to identify the most potent approach for organ protection as well as overlapping metabolic consequences has not been performed. We systematically analyzed six dietary preconditioning protocols - fasting mimicking diet (FMD), ketogenic diet (KD), dietary restriction of branched chained amino acids (BCAA), two dietary regimens restricting sulfur-containing amino acids (SR80/100) and CR - in a rodent model of renal ischemia-reperfusion injury (IRI) to quantify diet-induced resilience in kidneys. Of the administered diets, FMD, SR80/100 and CR efficiently protect from kidney damage after IRI. Interestingly, these approaches show overlapping changes in oxidative and hydrogen sulfide (H 2 S)-dependent cysteine catabolism as a potential common mechanism of organ protection. Importantly, these metabolic changes can be recapitulated in patients preconditioned by a diet limiting sulfur-containing amino acids indicating conserved diet-induced mechanisms of stress-resistance that may ultimately lead to clinical application.

Catabolism

Ketogenic Diet

10.1101/2021.09.08.459468

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Citations (1)

A systematic analysis of diet-induced nephroprotection reveals overlapping changes in cysteine catabolism

Translational research (2022)

Felix C. Koehler Chun-Yu Fu Martin R. Späth Karla Johanna Ruth Hoyer-Allo Katrin Bohl

Catabolism

Ketogenic Diet

10.1016/j.trsl.2022.02.003

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Citations (6)