Primary hepatocytes from mice lacking cysteine dioxygenase show increased cysteine concentrations and higher rates of metabolism of cysteine to hydrogen sulfide and thiosulfate

Jurkowska, Halina; Roman, Heather B.; Hirschberger, Lawrence L.; Sasakura, Kiyoshi; Nagano, Tetsuo; Hanaoka, Kenjiro; Krijt, Jakub; Stipanuk, Martha H.

doi:10.1007/s00726-014-1700-8

Cited by 34 publications

(32 citation statements)

References 55 publications

(93 reference statements)

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“…Liver thiosulfate was elevated in Cdo1 –/– mice, being 2.2–3.2 times the values for wild‐type controls. Elevated thiosulfate levels in Cdo1 –/– mice have been reported previously and are related to the excess flux of cysteine through desulfhydration pathways in the Cdo1 –/– mouse.…”

Section: Resultssupporting

confidence: 66%

Effects of a block in cysteine catabolism on energy balance and fat metabolism in mice

Niewiadomski

Zhou

Roman

et al. 2016

Annals of the New York Academy of Sciences

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To gain further insights into the effect of elevated cysteine levels on energy metabolism and the possible mechanisms by which cysteine may have these effects, we conducted studies in cysteine dioxygenase (Cdo1)–null mice. Cysteine dioxygenase (CDO) catalyzes the first step of the major pathway for cysteine catabolism. When CDO is absent, tissue and plasma cysteine levels are elevated, resulting in enhanced flux of cysteine through desulfhydration reactions. When Cdo1-null mice were fed a high-fat diet, they gained more weight than their wild-type controls, regardless of whether the diet was supplemented with taurine. Cdo1-null mice had markedly lower leptin levels, higher feed intakes, and markedly higher abundance of hepatic stearoyl-CoA desaturase 1 (SCD1) compared to wild-type control mice, and these differences were not affected by the fat or taurine content of the diet. Thus, reported associations of elevated cysteine levels with greater weight gain and with elevated hepatic Scd1 expression holds in the Cdo1-null mouse model. Hepatic accumulation of acylcarnitines suggested impaired mitochondrial β-oxidation of fatty acids in Cdo1-null mice. The strong associations of elevated cysteine levels with excess H2S production and impairments in energy metabolism suggest that H2S signaling could be involved.

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Section: Resultssupporting

confidence: 66%

Effects of a block in cysteine catabolism on energy balance and fat metabolism in mice

Niewiadomski

Zhou

Roman

et al. 2016

Annals of the New York Academy of Sciences

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“…Also reported in the CDO KO mice is an increase in the urinary excretion of thiosulfate, coupled with higher tissue and serum cystathionine and lanthionine levels. Importantly, the inhibition and destabilization of cytochrome c oxidase are observed that again is consistent with increased production of H 2 S [249, 250]. Thus, it would appear that the ability of CDO to control cysteine levels may be necessary to maintain low H 2 S/sulfane sulfur pools within tissues to facilitate the use of H 2 S as a signalling molecule [251].…”

Section: Cysteine Dioxygenase Knockout Mouse Modelsmentioning

confidence: 99%

H2S biosynthesis and catabolism: new insights from molecular studies

Rose

Moore

Zhu

2016

Cell. Mol. Life Sci.

146

100

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Hydrogen sulfide (H2S) has profound biological effects within living organisms and is now increasingly being considered alongside other gaseous signalling molecules, such as nitric oxide (NO) and carbon monoxide (CO). Conventional use of pharmacological and molecular approaches has spawned a rapidly growing research field that has identified H2S as playing a functional role in cell-signalling and post-translational modifications. Recently, a number of laboratories have reported the use of siRNA methodologies and genetic mouse models to mimic the loss of function of genes involved in the biosynthesis and degradation of H2S within tissues. Studies utilising these systems are revealing new insights into the biology of H2S within the cardiovascular system, inflammatory disease, and in cell signalling. In light of this work, the current review will describe recent advances in H2S research made possible by the use of molecular approaches and genetic mouse models with perturbed capacities to generate or detoxify physiological levels of H2S gas within tissues.

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“…However, despite the proposed central role of cysteine dioxygenase in cysteine homeostasis, a knockout of cysteine dioxygenase in mice surprisingly led to only a small increase in intracellular cysteine concentrations. Here, in the absence of cysteine dioxygenease, the non-oxidative desulfuration pathway was hypothesized to play a role in cysteine detoxification 22. Collectively, these data suggest the existence of other mechanisms to handle cysteine overload, which remain uninvestigated.…”

Section: Introductionmentioning

confidence: 95%

Thiol trapping and metabolic redistribution of sulfur metabolites enable cells to overcome cysteine overload

Deshpande¹,

Bhatia²,

Laxman³

et al. 2017

Microb Cell

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Cysteine is an essential requirement in living organisms. However, due to its reactive thiol side chain, elevated levels of intracellular cysteine can be toxic and therefore need to be rapidly eliminated from the cellular milieu. In mammals and many other organisms, excess cysteine is believed to be primarily eliminated by the cysteine dioxygenase dependent oxidative degradation of cysteine, followed by the removal of the oxidative products. However, other mechanisms of tackling excess cysteine are also likely to exist, but have not thus far been explored. In this study, we use Saccharomyces cerevisiae, which naturally lacks a cysteine dioxygenase, to investigate mechanisms for tackling cysteine overload. Overexpressing the high affinity cysteine transporter, YCT1, enabled yeast cells to rapidly accumulate high levels of intracellular cysteine. Using targeted metabolite analysis, we observe that cysteine is initially rapidly interconverted to non-reactive cystine in vivo. A time course revealed that cells systematically convert excess cysteine to inert thiol forms; initially to cystine, and subsequently to cystathionine, S-Adenosyl-L-homocysteine (SAH) and S-Adenosyl L-methionine (SAM), in addition to eventually accumulating glutathione (GSH) and polyamines. Microarray based gene expression studies revealed the upregulation of arginine/ornithine biosynthesis a few hours after the cysteine overload, and suggest that the non-toxic, non-reactive thiol based metabolic products are eventually utilized for amino acid and polyamine biogenesis, thereby enabling cell growth. Thus, cells can handle potentially toxic amounts of cysteine by a combination of thiol trapping, metabolic redistribution to non-reactive thiols and subsequent consumption for anabolism.

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Primary hepatocytes from mice lacking cysteine dioxygenase show increased cysteine concentrations and higher rates of metabolism of cysteine to hydrogen sulfide and thiosulfate

Cited by 34 publications

References 55 publications

Effects of a block in cysteine catabolism on energy balance and fat metabolism in mice

Effects of a block in cysteine catabolism on energy balance and fat metabolism in mice

H2S biosynthesis and catabolism: new insights from molecular studies

Thiol trapping and metabolic redistribution of sulfur metabolites enable cells to overcome cysteine overload

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