Evolution of energy metabolism and its compartmentation in Kinetoplastida

Kinetoplastida are protozoan organisms that probably diverged early in evolution from other eukaryotes. They are characterized by a number of unique features with respect to their energy and carbohydrate metabolism. These organisms possess peculiar peroxisomes, called glycosomes, which play a central role in this metabolism; the organelles harbour enzymes of several catabolic and anabolic routes, including major parts of the glycolytic and pentosephosphate pathways. The kinetoplastid mitochondrion is also unusual with regard to both its structural and functional properties. In this review, we describe the unique compartmentation of metabolism in Kinetoplastida and the metabolic properties resulting from this compartmentation. We discuss the evidence for our recently proposed hypothesis that a common ancestor of Kinetoplastida and Euglenida acquired a photosynthetic alga as an endosymbiont, contrary to the earlier notion that this event occurred at a later stage of evolution, in the Euglenida lineage alone. The endosymbiont was subsequently lost from the kinetoplastid lineage but, during that process, some of its pathways of energy and carbohydrate metabolism were sequestered in the kinetoplastid peroxisomes, which consequently became glycosomes. The evolution of the kinetoplastid glycosomes and the possible selective advantages of these organelles for Kinetoplastida are discussed. We propose that the possession of glycosomes provided metabolic flexibility that has been important for the organisms to adapt easily to changing environmental conditions. It is likely that metabolic flexibility has been an important selective advantage for many kinetoplastid species during their evolution into the highly successful parasites today found in many divergent taxonomic groups. Also addressed is the evolution of the kinetoplastid mitochondrion, from a supposedly pluripotent organelle, attributed to a single endosymbiotic event that resulted in all mitochondria and hydrogenosomes of extant eukaryotes. Furthermore, indications are presented that Kinetoplastida may have acquired other enzymes of energy and carbohydrate metabolism by various lateral gene transfer events different from those that involved the algal- and α-proteobacterial-like endosymbionts responsible for the respective formation of the glycosomes and mitochondria

Acetaminophen-induced acute liver injury in HCV transgenic mice

The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 hrs after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility

METABOLISM REPROGRAMMING IN HEXAVALENT CHROMIUM-INDUCED HUMAN LUNG CARCINOGENESIS

Hexavalent chromium, Cr(VI), is an established human carcinogen that is a worldwide environmental health concern. It is well understood that reactive oxygen species, genomic instability, and DNA damage repair deficiency are important contributors to Cr(VI)-induced carcinogenesis. After decades of research some cancer hallmarks remain understudied for the mechanism of Cr(VI) carcinogenesis. Dysregulated cellular energetics have been established as a hallmark of cancer. Energy pathways that become dysregulated in cancer include mitochondrial respiration, lipogenesis, pentose phosphate pathway, one carbon metabolism, and increased anaerobic glycolysis in the presence of oxygen or ‘Warburg effect’. To investigate metabolism changes in Cr(VI) carcinogenesis, we exposed human lung epithelial cells (BEAS-2B cells) to Cr(VI) for six months and isolated a colony from soft agar. To confirm the results in the BEAS-2B cells, we used two other sets of Cr(VI)-transformed cells, human lung epithelial cells (BEP2D cells) and human lung fibroblasts (WTHBF-6 cells). We found increased lipogenesis related protein expressions including: ATP citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FASN) in Cr(VI)-transformed cells as compared to passage-matched control cells. We also observed increased palmitic acid levels, confirming that Cr(VI)-transformed cells were making more lipids. Cr(VI)-transformed BEAS-2B cells had decreased colony formation in soft agar and decreased cell growth when treated with a FASN inhibitor (C75). ACLY, ACC1, and FASN protein expressions were also increased in chromate-induced lung tumors in human tissue samples. We also observed that Cr(VI)-transformed human lung cells (BEAS-2B, BEP2D, and WTHBF-6 cells) had no major changes in their mitochondrial respiration as measured by the Seahorse Analyzer when compared to their passage-matched control cells. Conversely, xenograft tumor-derived cells had mitochondrial respiratory dysfunction. Interestingly, we also found that Cr(VI)-transformed human lung cells (BEAS-2B, BEP2D, and WTHBF-6 cells) had no major changes in their glycolytic function as measured by the Seahorse Analyzer when compared to their passage-matched control cells. Similarly, these cells did not have changes in glycolytic enzymes or extracellular L-lactate levels. Moreover, xenograft tumor-derived cells showed no changes in glycolytic endpoints or L-lactate levels. This indicates these cells did not undergo the ‘Warburg effect’. These data demonstrate that increased lipogenesis is important to Cr(VI)-induced lung carcinogenesis and are consistent with the cancer literature which reports that increased lipogenesis proteins occur during carcinogenesis. Additionally, our results indicate mitochondrial respiratory dysfunction is likely a result of the tumor microenvironment and a later step during Cr(VI) carcinogenesis. Lastly, we observed the ‘Warburg effect’ is not required for Cr(VI)-induced carcinogenesis in vitro. However, it remains to be shown if the ‘Warburg effect’ is still a consequence or contributing factor for tumorigenesis. Future studies are needed to investigate other metabolic pathways in Cr(VI)-induced carcinogenesis. In conclusion, some metabolism pathways are important to Cr(VI)-induced carcinogenesis, while others appear not to be

How Streptococcus suis escapes antibiotic treatments

Streptococcus suis is a zoonotic agent that causes sepsis and meningitis in pigs and humans. S. suis infections are responsible for large economic losses in pig production. The lack of effective vaccines to prevent the disease has promoted the extensive use of antibiotics worldwide. This has been followed by the emergence of resistance against different classes of antibiotics. The rates of resistance to tetracyclines, lincosamides, and macrolides are extremely high, and resistance has spread worldwide. The genetic origin of S. suis resistance is multiple and includes the production of target-modifying and antibiotic-inactivating enzymes and mutations in antibiotic targets. S. suis genomes contain traits of horizontal gene transfer. Many mobile genetic elements carry a variety of genes that confer resistance to antibiotics as well as genes for autonomous DNA transfer and, thus, S. suis can rapidly acquire multiresistance. In addition, S. suis forms microcolonies on host tissues, which are associations of microorganisms that generate tolerance to antibiotics through a variety of mechanisms and favor the exchange of genetic material. Thus, alternatives to currently used antibiotics are highly demanded. A deep understanding of the mechanisms by which S. suis becomes resistant or tolerant to antibiotics may help to develop novel molecules or combinations of antimicrobials to fight these infections. Meanwhile, phage therapy and vaccination are promising alternative strategies, which could alleviate disease pressure and, thereby, antibiotic use.This work received funding from Gobierno de Aragón (Department of Science, University and Knowledge Society) for the development of I+D+i projects in priority lines (Grant agreement LMP58_21) and from Ministerio de Ciencia e Innovación/Agencia Española de Investigacion MCIN/ AEI/10.13039/501100011033 and, as appropriate, by “ERDF A way of making Europe”, by the “European Union” or by the “European Union NextGenerationEU/PRTR¨ (Grant agreement PID2020-114617RB-I00)

How Streptococcus suis escapes antibiotic treatments

Streptococcus suis is a zoonotic agent that causes sepsis and meningitis in pigs and humans. S. suis infections are responsible for large economic losses in pig production. The lack of effective vaccines to prevent the disease has promoted the extensive use of antibiotics worldwide. This has been followed by the emergence of resistance against different classes of antibiotics. The rates of resistance to tetracyclines, lincosamides, and macrolides are extremely high, and resistance has spread worldwide. The genetic origin of S. suis resistance is multiple and includes the production of target-modifying and antibiotic-inactivating enzymes and mutations in antibiotic targets. S. suis genomes contain traits of horizontal gene transfer. Many mobile genetic elements carry a variety of genes that confer resistance to antibiotics as well as genes for autonomous DNA transfer and, thus, S. suis can rapidly acquire multiresistance. In addition, S. suis forms microcolonies on host tissues, which are associations of microorganisms that generate tolerance to antibiotics through a variety of mechanisms and favor the exchange of genetic material. Thus, alternatives to currently used antibiotics are highly demanded. A deep understanding of the mechanisms by which S. suis becomes resistant or tolerant to antibiotics may help to develop novel molecules or combinations of antimicrobials to fight these infections. Meanwhile, phage therapy and vaccination are promising alternative strategies, which could alleviate disease pressure and, thereby, antibiotic use

Metformin

The book “Metformin” aims to bring to light new concepts and trends related to the many metformin therapeutic features. After a history of over 60 years, with moments of decline and spectacular returns, metformin can now be regarded as a universal panacea, the valences of its therapeutics being increasingly appreciated, both in the background treatment of diabetes and pre-diabetes, but also in reproductive pathology, cancer, cardiovascular disease, and antiageing. In this respect, the mechanisms of action and the pharmacodynamics of metformin seem to be incompletely known, a number of current studies have revealed new action valences

The clinical & metabolic correlates of fatigue in inflammatory arthritis & clinically suspect arthralgia

The earliest stages of inflammatory arthritis are associated with systemic inflammation and a complex set of symptoms including fatigue. Fatigue is common and burdensome. The mechanisms underlying fatigue are not well understood and, as a result, it is not always easy to manage. Systemic inflammation and metabolic perturbations may play a role in the development of fatigue. A correlation between systemic inflammation and metabolic perturbation has previously been observed in early inflammatory arthritis. While low-density lipoprotein lipids were some of the chief metabolites which contributed to the metabolic signature associated with systemic inflammation, technical limitations in those studies limited their ability to define more broadly other metabolic pathways involved. Given the likely importance of changes in metabolism to the development of fatigue, I set out to further analyse metabolic disturbance in an early arthritis cohort, assessing both sera, filtered to remove interfering high molecular weight species, and urine to provide a broader and clearer picture of the metabolic status of the patients. I have assessed the relationships between metabolic profiles and [1] systemic inflammation and [2] fatigue to shed further light on the drivers of fatigue in early inflammatory arthritis

How Streptococcus suis escapes antibiotic treatments

Streptococcus suis is a zoonotic agent that causes sepsis and meningitis in pigs and humans. S. suis infections are responsible for large economic losses in pig production. The lack of effective vaccines to prevent the disease has promoted the extensive use of antibiotics worldwide. This has been followed by the emergence of resistance against different classes of antibiotics. The rates of resistance to tetracyclines, lincosamides, and macrolides are extremely high, and resistance has spread worldwide. The genetic origin of S. suis resistance is multiple and includes the production of target-modifying and antibiotic-inactivating enzymes and mutations in antibiotic targets. S. suis genomes contain traits of horizontal gene transfer. Many mobile genetic elements carry a variety of genes that confer resistance to antibiotics as well as genes for autonomous DNA transfer and, thus, S. suis can rapidly acquire multiresistance. In addition, S. suis forms microcolonies on host tissues, which are associations of microorganisms that generate tolerance to antibiotics through a variety of mechanisms and favor the exchange of genetic material. Thus, alternatives to currently used antibiotics are highly demanded. A deep understanding of the mechanisms by which S. suis becomes resistant or tolerant to antibiotics may help to develop novel molecules or combinations of antimicrobials to fight these infections. Meanwhile, phage therapy and vaccination are promising alternative strategies, which could alleviate disease pressure and, thereby, antibiotic use