Universität zu Köln

Stucki, David ORCID: 0000-0002-0732-2761, Steinhausen, Julia, Westhoff, Philipp ORCID: 0000-0002-3494-9420, Krahl, Heide, Brilhaus, Dominik ORCID: 0000-0001-9021-3197, Massenberg, Annika, Weber, Andreas P. M., Reichert, Andreas S., Brenneisen, Peter and Stahl, Wilhelm (2020). Endogenous Carbon Monoxide Signaling Modulates Mitochondrial Function and Intracellular Glucose Utilization: Impact of the Heme Oxygenase Substrate Hemin. Antioxidants, 9 (8). BASEL: MDPI. ISSN 2076-3921

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Abstract

Stress-inducible heme oxygenase-1 (HO-1) catalyzes the oxidative cleavage of heme yielding biliverdin, ferrous iron, and carbon monoxide (CO). Heme oxygenase activity has been attributed to antioxidant defense via the redox cycling system of biliverdin and bilirubin. There is increasing evidence that CO is a gaseous signaling molecule and plays a role in the regulation of energy metabolism. Inhibitory effects of CO on the respiratory chain are well established, but the implication of such a process on the cellular stress response is not well understood. By means of extracellular flux analyses and isotopic tracing, we studied the effects of CO, either released from the CO donor CORM-401 or endogenously produced by heme oxygenases, on the respiratory chain and glucose metabolism. CORM-401 was thereby used as a tool to mimic endogenous CO production by heme oxygenases. In the long term (>60 min), CORM-401-derived CO exposure inhibited mitochondrial respiration, which was compensated by increased glycolysis accompanied by a loss of the ATP production rate and an increase in proton leakage. This effect pattern was likewise observed after endogenous CO production by heme oxygenases. However, in the present setting, these effects were only observed when sufficient substrate for heme oxygenases (hemin) was provided. Modulation of the HO-1 protein level was less important. The long-term influence of CO on glucose metabolism via glycolysis was preceded by a short-term response (<30 min) of the cells to CO. Stable isotope-labeling experiments and metabolic flux analysis revealed a short-term shift of glucose consumption from glycolysis to the pentose phosphate pathway (PPP) along with an increase in reactive oxygen species (ROS) generation. Overall, we suggest that signaling by endogenous CO stimulates the rapid formation of reduction equivalents (NADPH) via the PPP, and plays an additional role in antioxidant defense, e.g., via feed-forward stimulation of the bilirubin/biliverdin redox cycling system.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stucki, David UNSPECIFIED orcid.org/0000-0002-0732-2761 UNSPECIFIED Steinhausen, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Westhoff, Philipp UNSPECIFIED orcid.org/0000-0002-3494-9420 UNSPECIFIED Krahl, Heide UNSPECIFIED UNSPECIFIED UNSPECIFIED Brilhaus, Dominik UNSPECIFIED orcid.org/0000-0001-9021-3197 UNSPECIFIED Massenberg, Annika UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Andreas P. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reichert, Andreas S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brenneisen, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Stahl, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-324550
DOI:	10.3390/antiox9080652
Journal or Publication Title:	Antioxidants
Volume:	9
Number:	8
Date:	2020
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2076-3921
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CYTOCHROME-C-OXIDASE; ENDOTHELIAL-CELLS; BILIRUBIN; CORM-401; EXPOSURE; MICE; METABOLISM; EXCHANGE Multiple languages Biochemistry & Molecular Biology; Chemistry, Medicinal; Food Science & Technology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32455