SFRR Young Investigator Award

HEPATIC METHANETHIOL OXIDASE ACTIVITY IS AT-TENUATED IN RODENTS HELD UNDER COPPER DEFI-CIENCY BUT UNALTERED BY COPPER OVERLOAD

Niklas Krafczyk¹, Alina Löser², Kristina Loßow², Hans Zischka^3,4, Holger Steinbrenner¹, Anna Patricia Kipp², Lars-Oliver Klotz¹

¹Institute of Nutritional Sciences, Nutrigenomics Section, Friedrich Schiller University Jena, Jena, Germany
²Institute of Nutritional Sciences, Department of Nutritional Physiology, Friedrich Schiller University Jena, Jena, Germany
³Institute of Toxicology and Environmental Hygiene, Technical University Munich School of Medicine and Health, Munich, Germany
⁴Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

Abstract

Introduction: Copper (Cu) is an essential trace element that can serve as cofactor in several oxidoreductases. Selenium-binding protein 1 (SELENBP1), identified originally through its binding of selenite, is a me-thanethiol oxidase (MTO), catalyzing the conversion of methanethiol to hy-drogen sulfide, hydrogen peroxide and formaldehyde. Recently, we demon-strated that selenium was dispensable for the MTO activity of SELENBP1, whereas it required Cu ions [1].
Objective: With SELENBP1 being a Cu-dependent MTO, we asked to what extent dietary Cu availability translates into enzyme activity in vivo.
Methods: We analyzed SELENBP1 levels and MTO activity in liver samples obtained from mice fed a diet deficient in Cu, either with or without addi-tional deficiencies in selenium and/or zinc, for eight weeks and compared these to mice with adequate trace element supply.
Results: All Cu-deficient diets resulted in diminished MTO activity in the liv-er of both male and female mice. Regarding hepatic SELENBP1 levels, a sex-specific effect was observed: whereas diets deficient either in Cu or selenium as well as the combination of both increased SELENBP1 levels in males, levels were decreased as a consequence of Cu- and zinc-deficient conditions in females. In line with the Cu-dependence of SELENBP1 en-zyme activity, MTO activity in human HepG2 hepatoma cells was de-creased upon treatment with the Cu chelator bathocuproinedisulfonate. In contrast to the suppressive effect of Cu deficiency, MTO activity remained unchanged in response to excessive hepatic Cu accumulation, as evi-denced in a rat model of Wilson’s disease.
Conclusion: In conclusion, hepatic MTO activity exhibits a greater sensitivi-ty to Cu deficiency than to Cu overload, suggesting a saturation under con-ditions of adequate dietary Cu availability.

[1] Philipp TM, Gernoth L, Will A, Schwarz M, Ohse VA, Kipp AP, Steinbrenner H, Klotz LO. (2023): Selenium-binding protein 1 (SELENBP1) is a copper-dependent thiol oxidase. Redox Biolo-gy. 65:102807.