Changes in TCA cycle and TCA cycle-related metabolites in plasma upon citric acid administration in rats

ABSTRACT Screening the Saccharomyces cerevisiae disruptome, profiling transcripts, and determining changes in protein expression have identified an important new role for the high-osmolarity glycerol (HOG) mitogen-activated protein kinase (MAPK) pathway in the regulation of adaptation to citric acid stress. Deletion of HOG1, SSK1, PBS2, PTC2, PTP2, and PTP3 resulted in sensitivity to citric acid. Furthermore, citric acid resulted in the dual phosphorylation, and thus activation, of Hog1p. Despite minor activation of glycerol biosynthesis, the inhibitory effect of citric acid was not due to an osmotic shock. HOG1 negatively regulated the expression of a number of proteins in response to citric acid stress, including Bmh1p. Evidence suggests that BMH1 is induced by citric acid to counteract the effect of amino acid starvation. In addition, deletion of BMH2 rendered cells sensitive to citric acid. Deletion of the transcription factor MSN4, which is known to be regulated by Bmh1p and Hog1p, had a similar effect. HOG1 was also required for citric acid-induced up-regulation of Ssa1p and Eno2p. To counteract the cation chelating activity of citric acid, the plasma membrane Ca2+ channel, CCH1, and a functional vacuolar membrane H+-ATPase were found to be essential for optimal adaptation. Also, the transcriptional regulator CYC8, which mediates glucose derepression, was required for adaptation to citric acid to allow cells to metabolize excess citrate via the tricarboxylic acid (TCA) cycle. Supporting this, Mdh1p and Idh1p, both TCA cycle enzymes, were up-regulated in response to citric acid.

Download Full-text

Citric acid promoted melanin synthesis in B16F10 mouse melanoma cells, but inhibited it in human epidermal melanocytes and HMV-II melanoma cells via the GSK3β/β-catenin signaling pathway

PLoS ONE ◽

10.1371/journal.pone.0243565 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0243565

Author(s):

Siqi Zhou ◽

Kazuichi Sakamoto

Keyword(s):

Citric Acid ◽

Signaling Pathway ◽

Glycogen Synthase ◽

Tca Cycle ◽

Underlying Mechanism ◽

Melanoma Cells ◽

Human Cells ◽

Ultraviolet Rays ◽

Melanin Synthesis ◽

Mouse Cells

Melanin, a pigment synthesized by melanocytes in the skin, resists the damage caused by ultraviolet rays to cells. Citric acid, a well-known food additive, is commonly used as an antioxidant and is an important part of the tricarboxylic acid (TCA) cycle for energy production during cellular metabolism. Here, we aimed to investigate whether the addition of excess citric acid regulates melanin synthesis, and to delineate the underlying mechanism. First, we observed that citric acid exerts opposite redox effects on mouse and human cells. Interestingly, treatment with excess citric acid increased the melanin content in mouse cells but decreased it in human cells. Furthermore, the expression of factors important for melanin synthesis, such as microphthalmia-associated transcription factor (MITF), was also regulated by citric acid treatment—it was promoted in mouse cells and suppressed in human cells. Citric acid also impacted the upstream regulators of MITF, glycogen synthase kinase 3β (GSK3β), and β-catenin. Second, we determined the importance of GSK3β in the citric acid-mediated regulation of melanin synthesis, using a GSK3β inhibitor (BIO). To the best of our knowledge, this is the first study to show that citric acid regulates melanin synthesis via the GSK3β/β-catenin signaling pathway, and that equal amounts of exogenous citric acid exert opposing effects on mouse and human cells.

Download Full-text

Expression of Genes Related to Glycolysis in the Liver and Skeletal Muscle of Rats after Citric Acid Administration

Food and Nutrition Sciences ◽

10.4236/fns.2019.103025 ◽

2019 ◽

Vol 10 (03) ◽

pp. 325-332

Author(s):

Yurie Hara ◽

Nakamichi Watanabe

Keyword(s):

Skeletal Muscle ◽

Citric Acid ◽

Expression Of Genes ◽

Acid Administration

Download Full-text

A Dysfunctional Tricarboxylic Acid Cycle Enhances Fitness of Staphylococcus epidermidis During β-Lactam Stress

mBio ◽

10.1128/mbio.00437-13 ◽

2013 ◽

Vol 4 (4) ◽

Cited By ~ 12

Author(s):

Vinai Chittezham Thomas ◽

Lauren C. Kinkead ◽

Ashley Janssen ◽

Carolyn R. Schaeffer ◽

Keith M. Woods ◽

...

Keyword(s):

Oxidative Stress ◽

Citric Acid ◽

Cell Surface ◽

Staphylococcus Epidermidis ◽

Citric Acid Cycle ◽

Tricarboxylic Acid Cycle ◽

Tca Cycle ◽

Tricarboxylic Acid ◽

Content Type ◽

Acid Cycle

ABSTRACT A recent controversial hypothesis suggested that the bactericidal action of antibiotics is due to the generation of endogenous reactive oxygen species (ROS), a process requiring the citric acid cycle (tricarboxylic acid [TCA] cycle). To test this hypothesis, we assessed the ability of oxacillin to induce ROS production and cell death in Staphylococcus epidermidis strain 1457 and an isogenic citric acid cycle mutant. Our results confirm a contributory role for TCA-dependent ROS in enhancing susceptibility of S. epidermidis toward β-lactam antibiotics and also revealed a propensity for clinical isolates to accumulate TCA cycle dysfunctions presumably as a way to tolerate these antibiotics. The increased protection from β-lactam antibiotics could result from pleiotropic effects of a dysfunctional TCA cycle, including increased resistance to oxidative stress, reduced susceptibility to autolysis, and a more positively charged cell surface. IMPORTANCE Staphylococcus epidermidis, a normal inhabitant of the human skin microflora, is the most common cause of indwelling medical device infections. In the present study, we analyzed 126 clinical S. epidermidis isolates and discovered that tricarboxylic acid (TCA) cycle dysfunctions are relatively common in the clinical environment. We determined that a dysfunctional TCA cycle enables S. epidermidis to resist oxidative stress and alter its cell surface properties, making it less susceptible to β-lactam antibiotics.

Download Full-text

The Glyoxylate Shunt, 60 Years On

Annual Review of Microbiology ◽

10.1146/annurev-micro-090817-062257 ◽

2018 ◽

Vol 72 (1) ◽

pp. 309-330 ◽

Cited By ~ 34

Author(s):

Stephen K. Dolan ◽

Martin Welch

Keyword(s):

Citric Acid ◽

Citric Acid Cycle ◽

Tca Cycle ◽

Oxidative Decarboxylation ◽

Glyoxylate Shunt ◽

Cellular Functions ◽

Acid Cycle ◽

E Coli ◽

80Th Anniversary ◽

The Tca Cycle

2017 marks the 60th anniversary of Krebs’ seminal paper on the glyoxylate shunt (and coincidentally, also the 80th anniversary of his discovery of the citric acid cycle). Sixty years on, we have witnessed substantial developments in our understanding of how flux is partitioned between the glyoxylate shunt and the oxidative decarboxylation steps of the citric acid cycle. The last decade has shown us that the beautifully elegant textbook mechanism that regulates carbon flux through the shunt in E. coli is an oversimplification of the situation in many other bacteria. The aim of this review is to assess how this new knowledge is impacting our understanding of flux control at the TCA cycle/glyoxylate shunt branch point in a wider range of genera, and to summarize recent findings implicating a role for the glyoxylate shunt in cellular functions other than metabolism.

Download Full-text

Influence of impeller speed on citric acid production and selected enzyme activities of the TCA cycle

Journal of Industrial Microbiology ◽

10.1007/bf01575887 ◽

1991 ◽

Vol 7 (3) ◽

pp. 221-225 ◽

Cited By ~ 6

Author(s):

T. Roukas

Keyword(s):

Citric Acid ◽

Enzyme Activities ◽

Acid Production ◽

Tca Cycle ◽

Impeller Speed ◽

Citric Acid Production ◽

The Tca Cycle

Download Full-text

Influence of Citric Acid Administration upon Renal Ammoniagenesis in the Acidotic Dog and Rat

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y72-127 ◽

1972 ◽

Vol 50 (9) ◽

pp. 883-889 ◽

Cited By ~ 4

Author(s):

Tomas C. Welbourne

Keyword(s):

Citric Acid ◽

Acid Level ◽

Rat Kidney ◽

Ammonia Production ◽

Kidney Slices ◽

Dog Kidney ◽

Acid Administration

Citric acid reduced ammoniagenesis both in vitro and in vivo by the acidotic dog kidney. In the dog, renal cortical levels of citric acid, α-ketoglutaric acid (α-KG), glutamate, and glutamine were lower in the acidotic than nonacidotic state. Citric acid administration elevated tissue citric acid level 10-fold above the acidotic level, but levels of α-KG, glutamate, and glutamine remained unchanged. In kidney slices taken from acidotic dogs, citric acid levels were greatly elevated reducing ammonia production but failing to increase tissue glutamate. In the acidotic rat kidney, citric acid inhibited ammoniagenesis by incorporating ammonia into glutamate and glutamine. Although citric acid reduces ammoniagenesis in both acidotic rat and dog kidney, the rat kidney produces glutamine and glutamate while the dog kidney does not; consequently the mechanism by which citric acid influences ammoniagenesis appears to differ in the species.

Download Full-text