Bacteroides vulgatus SNUG 40005 Restores Akkermansia Depletion by Metabolite Modulation.

BACKGROUND & AIMS: Weight loss and exercise intervention have been reported to increase the interaction between Bacteroides spp and Akkermansiamuciniphila (Am), although the underlying mechanisms and consequences of the interaction remain unknown. METHODS: Using a healthy Korean twin cohort (n = 582), we analyzed taxonomic associations with host body mass index. B vulgatus strains were isolated from mice and human subjects to investigate the strain-specific effect of B vulgatus SNUG 40005 (Bvul) on obesity. The mechanisms underlying Am enrichment by Bvul administration were investigated by multiple experiments: (1) in vitro cross-feeding experiments, (2) construction of Bvul mutants with the N-acetylglucosaminidase gene knocked out, and (3) in vivo validation cohorts with different metabolites. Finally, metabolite profiling in mouse and human fecal samples was performed. RESULTS: An interaction between Bvul and Am was observed in lean subjects but was disrupted in obese subjects. The administration of Bvul to mice fed a high-fat diet decreased body weight, insulin resistance, and gut permeability. In particular, Bvul restored the abundance of Am, which decreased significantly after a long-term high-fat diet. A cross-feeding analysis of Am with cecal contents or Bvul revealed that Am enrichment was attributed to metabolites produced during mucus degradation by Bvul. The metabolome profile of mouse fecal samples identified N-acetylglucosamine as contributing to Am enrichment, which was confirmed by in vitro and in vivo experiments. Metabolite network analysis of the twin cohort found that lysine serves as a bridge between N-acetylglucosamine, Bvul, and Am. CONCLUSIONS: Strain-specific microbe-microbe interactions modulate the mucosal environment via metabolites produced during mucin degradation in the gut.

Assessment of gastrointestinal function and its' effect on bone mineral density and body composition in hypermobility spectrum disorder and hypermobile Ehlers-Danlos syndrome.

BACKGROUND: Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorders (HSD) are associated with hypermobility, musculoskeletal pain, a decreased bone mineral density (BMD) and gastrointestinal (GI) complications. The role of GI symptoms and diet in BMD has not been established in this population. The GI complications can lead to an energy deficit due to lack of essential macronutrients. The primary objective of this study was to determine the severity of GI symptoms compared to body composition and BMD in individuals with hEDS/HSD. The secondary objective is to examine GI symptoms on energy balance, body composition and strength. METHODOLOGY: This study was IRB approved. Eighteen female participants (aged 28.2 ± 4.9; BMI 22.5 ± 4.9) with a diagnosis of hEDS or HSD and 18 female healthy control participants (aged 28.1 ± 3.8; BMI 22.8 ±3.9) signed consent to participate. Participants were matched by sex, age, and BMI. The Gastrointestinal Symptom Rating Scale (GSRS) was used to investigate severity of GI symptoms. Dual X-ray absorptiometry was used to determine body composition (body fat%, lean body mass (LBM). BMD was measured by Z- scores of both femurs and lumbar spine. Resting metabolic rate (RMR) was measured using indirect calorimetry and strength was determined using a hand grip dynamometer. RESULTS: All hEDS/HSD participants reported GI symptoms. There was no difference in body composition between hEDS/HSD and controls. Participants with hEDS/HSD had lower BMD both femoral z scores (p=0.02,0.004) and spine z scores (p= 0.04). There was no difference in caloric intake between groups; yet both groups demonstrated caloric deficits. Additionally, hEDS/HSD consumed less protein and more carbohydrates (p=0.03, p=0.03). There were no differences in grip strength. CONCLUSIONS: This study identified that pre-menopausal women with hEDS/HSD presented with significant GI complications and lower BMD than age matched controls. The GI complications and the reduced protein intake long-term may have a lasting impact on bone health. This study found that the GSRS identified and quantified GI symptoms in persons with hEDS/HSD. Future studies are needed for the longitudinal effects of a caloric/protein deficit in this population and to help guide future preventive and nutritional treatment approaches in individuals with hEDS/HSD.

Methods in sulfide and persulfide research.

Sulfides and persulfides/polysulfides (R-Sn-R', n > 2; R-Sn-H, n > 1) are endogenously produced metabolites that are abundant in mammalian and human cells and tissues. The most typical persulfides that are widely distributed among different organisms include various reactive persulfides-low-molecular-weight thiol compounds such as cysteine hydropersulfide, glutathione hydropersulfide, and glutathione trisulfide as well as protein-bound thiols. These species are generally more redox-active than are other simple thiols and disulfides. Although hydrogen sulfide (H2S) has been suggested for years to be a small signaling molecule, it is intimately linked biochemically to persulfides and may actually be more relevant as a marker of functionally active persulfides. Reactive persulfides can act as powerful antioxidants and redox signaling species and are involved in energy metabolism. Recent evidence revealed that cysteinyl-tRNA synthetases (CARSs) act as the principal cysteine persulfide synthases in mammals and contribute significantly to endogenous persulfide/polysulfide production, in addition to being associated with a battery of enzymes including cystathionine ß-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase, which have been described as H2S-producing enzymes. The reactive sulfur metabolites including persulfides/polysulfides derived from CARS2, a mitochondrial isoform of CARS, also mediate not only mitochondrial biogenesis and bioenergetics but also anti-inflammatory and immunomodulatory functions. The physiological roles of persulfides, their biosynthetic pathways, and their pathophysiology in various diseases are not fully understood, however. Developing basic and high precision techniques and methods for the detection, characterization, and quantitation of sulfides and persulfides is therefore of great importance so as to thoroughly understand and clarify the exact functions and roles of these species in cells and in vivo.

Phase Controlled Growth of Cd3As2 Nanowires and Their Negative Photoconductivity.

The bottom-up synthesis process often allows the growth of metastable phase nanowires instead of the thermodynamically stable phase. Herein, we synthesized Cd3As2 nanowires with a controlled three-dimensional Dirac semimetal phase using a chemical vapor transport method. Three different phases such as the body centered tetragonal (bct), and two metastable primitive tetragonal (P42/nbc and P42/nmc) phases were identified. The conversion between three phases (bct → P42/nbc → P42/nmc) was achieved by increasing the growth temperature. The growth direction is [110] for bct and P42/nbc and [100] for P42/nmc, corresponding to the same crystallographic axis. Field effect transistors and photodetector devices showed the nearly same electrical and photoelectrical properties for three phases. Differential conductance measurement confirms excellent electron mobility (2 × 104 cm2/(V s) at 10 K). Negative photoconductance was first observed, and the photoresponsivity reached 3 × 104 A/W, which is ascribed to the surface defects acting as trap sites for the photogenerated electrons.

Mitochondrial cysteinyl-tRNA synthetase is expressed via alternative transcriptional initiation regulated by energy metabolism in yeast cells.

Eukaryotes typically utilize two distinct aminoacyl-tRNA synthetase isoforms, one for cytosolic and one for mitochondrial protein synthesis. However, the genome of budding yeast (Saccharomyces cerevisiae) contains only one cysteinyl-tRNA synthetase gene (YNL247W, also known as CRS1). In this study, we report that CRS1 encodes both cytosolic and mitochondrial isoforms. The 5' complementary DNA end method and GFP reporter gene analyses indicated that yeast CRS1 expression yields two classes of mRNAs through alternative transcription starts: a long mRNA containing a mitochondrial targeting sequence and a short mRNA lacking this targeting sequence. We found that the mitochondrial Crs1 is the product of translation from the first initiation AUG codon on the long mRNA, whereas the cytosolic Crs1 is produced from the second in-frame AUG codon on the short mRNA. Genetic analysis and a ChIP assay revealed that the transcription factor heme activator protein (Hap) complex, which is involved in mitochondrial biogenesis, determines the transcription start sites of the CRS1 gene. We also noted that Hap complex-dependent initiation is regulated according to the needs of mitochondrial energy production. The results of our study indicate energy-dependent initiation of alternative transcription of CRS1 that results in production of two Crs1 isoforms, a finding that suggests Crs1's potential involvement in mitochondrial energy metabolism in yeast.

Controllable p-n junctions in three-dimensional Dirac semimetal Cd3As2 nanowires.

We demonstrate a controllable p-n junction in a three-dimensional Dirac semimetal (DSM) Cd3As2 nanowire with two recessed bottom gates. The device exhibits four different conductance regimes with gate voltages, the unipolar (n-n and p-p) and bipolar (n-p and n-p) regimes, where p-n junctions are formed. The conductance in the p-n junction regimes decreases drastically when a magnetic field is applied perpendicular to the nanowire. In these regimes, the device shows quantum dot behavior, whereas the device exhibits conductance plateaus in the n-n regime at high magnetic fields. Our experiment shows that the ambipolar tunability of DSM nanowires can enable the realization of quantum devices based on quantum dots and electron optics.

Nicotine Gum as a Therapeutic Approach for Low Blood Pressure in Parkinson's Disease: A Randomized Pilot Study.

Introduction: One cause for low blood pressure (BP) in Parkinson's disease (PD) is denervation of the sympathetic nervous system and reduced levels of norepinephrine. Nicotine increases heart rate and BP acutely by causing sympathetic stimulation. The absorption rate of nicotine gum is relatively quick and absorbed at a constant rate. Our objective was to evaluate how nicotine gum affects acute low BP in PD. Methods: Ten subjects (age 69.3 ± 8.8) completed this double blind, placebo controlled, cross-over design trial using nicotine gum (4 mg) and placebo gum on two separate days. The gum was administered for 30 min. BP was recorded every 10 min for 90 min. Results: On the nicotine gum treatment day, the baseline systolic BP was 94.8 (standard deviation [SD] = 4.4), and it increased in a parabolic pattern to be 115.8 (SD = 11.2) in 20 min, 124.2 (SD = 9.3) in 40 min, and 133.2 (SD = 13.1) in 60 min reaching the highest value, and then decreased to be 121.6 (SD = 10.4) in 90 min. On the placebo day, the baseline systolic BP 95.2 (SD = 3.0) didn't show an outstanding change with the mean systolic BP values from 93.0 to 95.7 (SD from 2.1 to 3.7) at all time points. Conclusions: Our data suggests that 4 mg of nicotine gum can increase systolic BP within 10 min of administration. It is strongly warranted that further research should pursue the use of nicotine gum as an intervention to treat acute episodes of low BP in individuals with PD. Implications: More than 50% of Parkinson's disease (PD) patients have low blood pressure (BP) that fluctuates throughout the day and decreases quality of life. This study found an increase in systolic blood pressure within 10 min of administering nicotine gum to Parkinson's subjects with low BP. Their BP remained elevated for 90 min. Nicotine gum gets absorbed rapidly and may act as a therapeutic novel approach to individuals whose daily lives are interrupted with low BP.

Quantum Dots Formed in Three-dimensional Dirac Semimetal Cd3As2 Nanowires.

We demonstrate quantum dot (QD) formation in three-dimensional Dirac semimetal Cd3As2 nanowires using two electrostatically tuned p-n junctions with a gate and magnetic fields. The linear conductance measured as a function of gate voltage under high magnetic fields is strongly suppressed at the Dirac point close to zero conductance, showing strong conductance oscillations. Remarkably, in this regime, the Cd3As2 nanowire device exhibits Coulomb diamond features, indicating that a clean single QD forms in the Dirac semimetal nanowire. Our results show that a p-type QD can be formed between two n-type leads underneath metal contacts in the nanowire by applying gate voltages under strong magnetic fields. Analysis of the quantum confinement in the gapless band structure confirms that p-n junctions formed between the p-type QD and two neighboring n-type leads under high magnetic fields behave as resistive tunnel barriers due to cyclotron motion, resulting in the suppression of Klein tunneling. The p-type QD with magnetic field-induced confinement shows a single hole filling. Our results will open up a route to quantum devices such as QDs or quantum point contacts based on Dirac and Weyl semimetals.

Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells.

Electrophiles such as methylmercury (MeHg) affect cellular functions by covalent modification with endogenous thiols. Reactive persulfide species were recently reported to mediate antioxidant responses and redox signaling because of their strong nucleophilicity. In this study, we used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of the endogenous electrophilic molecule 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), accompanied by depletion of reactive persulfide species and 8-SH-cGMP which is a metabolite of 8-nitro-cGMP. Exposure to MeHg also induced S-guanylation and activation of H-Ras followed by injury to cerebellar granule neurons. The electrophile-induced activation of redox signaling and the consequent cell damage were attenuated by pretreatment with a reactive persulfide species donor. In conclusion, exogenous electrophiles such as MeHg with strong electrophilicity impair the redox signaling regulatory mechanism, particularly of intracellular reactive persulfide species and therefore lead to cellular pathogenesis. Our results suggest that reactive persulfide species may be potential therapeutic targets for attenuating cell injury by electrophiles.

Microwave Photodetection in an Ultraclean Suspended Bilayer Graphene p-n Junction.

We explore the potential of bilayer graphene as a cryogenic microwave photodetector by studying the microwave absorption in fully suspended clean bilayer graphene p-n junctions in the frequency range of 1-5 GHz at a temperature of 8 K. We observe a distinct photocurrent signal if the device is gated into the p-n regime, while there is almost no signal for unipolar doping in either the n-n or p-p regimes. Most surprisingly, the photocurrent strongly peaks when one side of the junction is gated to the Dirac point (charge-neutrality point CNP), while the other remains in a highly doped state. This is different to previous results where optical radiation was used. We propose a new mechanism based on the phototermal effect explaining the large signal. It requires contact doping and a distinctly different transport mechanism on both sides: one side of graphene is ballistic and the other diffusive. By engineering partially diffusive and partially ballistic devices, the photocurrent can drastically be enhanced.

Endogenous occurrence of protein S-guanylation in Escherichia coli: Target identification and genetic regulation.

8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is a nitrated cGMP derivative formed in response to nitric oxide (NO) and reactive oxygen species (ROS). It can cause a post-translational modification (PTM) of protein thiols through cGMP adduction (protein S-guanylation). Accumulating evidence has suggested that, in mammals, S-guanylation of redox-sensor proteins may implicate in regulation of adaptive responses against ROS-associated oxidative stress. Occurrence as well as protein targets of S-guanylation in bacteria remained unknown, however. Here we demonstrated, for the first time, the endogenous occurrence of protein S-guanylation in Escherichia coli (E. coli). Western blotting using anti-S-guanylation antibody clearly showed that multiple proteins were S-guanylated in E. coli. Interestingly, some of those proteins were more intensely S-guanylated when bacteria were cultured under static culture condition than shaking culture condition. It has been known that E. coli is deficient of guanylate cyclase, an enzyme indispensable for 8-nitro-cGMP formation in mammals. We found that adenylate cyclase from E. coli potentially catalyzed 8-nitro-cGMP formation from its precursor 8-nitroguanosine 5'-triphosphate. More importantly, E. coli lacking adenylate cyclase showed significantly reduced formation of S-guanylated proteins. Our S-guanylation proteomics successfully identified S-guanylation protein targets in E. coli, including chaperons, ribosomal proteins, and enzymes which associate with protein synthesis, redox regulation and metabolism. Understanding of functional impacts for protein S-guanylation in bacterial signal transduction is necessary basis for development of potential chemotherapy and new diagnostic strategy for control of pathogenic bacterial infections.

Protein polysulfidation-dependent persulfide dioxygenase activity of ethylmalonic encephalopathy protein 1.

Reactive persulfide species such as glutathione persulfide (GSSH) are highly abundant biomolecules. Persulfide dioxygenase (also called ethylmalonic encephalopathy protein 1, ETHE1) reportedly metabolizes GSSH to GSH with simultaneous oxygen consumption. How ETHE1 activity is regulated is still unclear, however. In this study, we describe the possible role of protein polysulfidation in the catalytic activity of ETHE1. We first found that ETHE1 catalyzed the persulfide dioxygenase reaction mostly for glutathione polysulfides, GS-(S)n-H, as well as for GSSH, but not for other endogenous persulfides such as cysteine and homocysteine persulfides/polysulfides. We then developed a novel method to detect protein polysulfidation and named it the polyethylene glycol-conjugated maleimide-labeling gel shift assay (PMSA). PMSA analysis indicated that most cysteine residues in ETHE1 were polysulfidated. Site-directed mutagenesis of cysteine residues in ETHE1 combined with liquid chromatography tandem mass spectrometry for polysulfidation determination surprisingly indicated that the Cys247 residue was important for polysulfidation of other Cys residues and that the C247S mutant possessed no persulfide dioxygenase activity. These results suggested that ETHE1 is a major enzyme regulating endogenous GSSH/GS-(S)n-H and that its activity is controlled by polysulfidation of the Cys247 residue.

Physician Risk Assessment Knowledge Regarding BRCA Genetics Testing.

The study aim was to evaluate the association between genetics referrals, training in medical school, residency, or continuing medical education and physician knowledge of hereditary breast and ovarian cancer (HBOC). A survey of 55 questions was administered to 140 physicians evaluating knowledge and practice patterns regarding HBOC. Physicians with genetics training during residency were more likely to recognize that most instances of ovarian cancer are not hereditary (odds ratio (OR) = 3.16; 95 % confidence interval (CI) 1.32, 7.58). Physicians with continuing medical education (CME) training on genetics were more likely to identify that screening can be improved for those with a hereditary mutation (OR = 4.28; 95 % CI 1.32, 13.90). Primary care physicians who frequently referred for genetics were more likely to recognize that maternal history is not more important than paternal history (OR = 2.51; 95 % CI 1.11, 5.66), that screening can be improved for those with hereditary risk (OR = 4.06; 95 % CI 1.08, 15.22), and that females with a hereditary breast cancer risk would have different recommendations for screening than someone without this risk (OR = 4.91; 95 % CI 1.04, 23.25). Our data suggest that training and frequency of genetics referrals may be associated with knowledge of general risk assessment for HBOC.

Ultraclean single, double, and triple carbon nanotube quantum dots with recessed Re bottom gates.

We demonstrate that ultraclean single, double, and triple quantum dots (QDs) can be formed reliably in a carbon nanotube (CNT) by a straightforward fabrication technique. The QDs are electrostatically defined in the CNT by closely spaced metallic bottom gates deposited in trenches in SiO2 by sputter deposition of Re. The carbon nanotubes are then grown by chemical vapor deposition (CVD) across the trenches and contacted using conventional resist-based electron beam lithography. Unlike in previous work, the devices exhibit reproducibly the characteristics of ultraclean QDs behavior even after the subsequent electron beam lithography and chemical processing steps. We specifically demonstrate the high quality using CNT devices with two narrow bottom gates and one global back gate. Tunable by the gate voltages, the device can be operated in four different regimes: (i) fully p-type with ballistic transport between the outermost contacts (over a length of 700 nm), (ii) clean n-type single QD behavior where a QD can be induced by either the left or the right bottom gate, (iii) n-type double QD, and (iv) triple bipolar QD where the middle QD has opposite doping (p-type). Our simple fabrication scheme opens up a route to more complex devices based on ultraclean CNTs, since it allows for postgrowth processing.

Clinical Site Visits: Perspectives of Clinical Instructors and Site Coordinators of Clinical Education.

INTRODUCTION: Site visits (SVs) are a common component of clinical education. The purpose of this paper was to explore clinicians' perspectives regarding SVs, including methods of communication used and their effectiveness, purposes of SVs, and the level of interaction between the stakeholders. REVIEW OF THE LITERATURE: Several communication methods are used to conduct SVs, with varying levels of "richness" and effectiveness. Previous studies have explored the perceptions of physical therapist (PT) students and Directors of Clinical Education regarding communication methods used during SVs, as well as reporting the purposes, effectiveness, and logistics. SUBJECTS: Clinicians, including clinical instructors (CIs) and Site Coordinators of Clinical Education, from across the United States, representing various geographical locations and settings were invited to participate. METHODS: An electronic survey was distributed to participants using information from 2 PT education programs and the Physical Therapist Clinical Performance Instrument database. RESULTS: A total of 273 responses were included in the analysis. Clinicians ranked in-person visits as their first choice of communication for future SVs (n = 157, 59.9%) and indicated that in-person communication was "very effective" (n = 143, 52.4%) when compared with videoconferencing (n = 55, 20.1%) and telephone (n = 49, 17.9%). Clinicians ranked verifying the competency level of the student and verifying site resources during the SV as "extremely important" or "important" (n = 257, 94.2% and n = 250, 91.5%, respectively). Answering CI's questions and providing support to the CI were also identified as "extremely important" or "important" (n = 262, 96% and n = 244, 89.4%, respectively). Analysis of open-ended responses revealed 5 themes: Communication is important, flexibility allows best fit for a situation, on-site visits offer a more complete picture, real-time dialog is preferred, and email can lead to misinterpretation. DISCUSSION AND CONCLUSION: Communication is a key component of the clinical-academic relationship. Although clinicians prefer in-person communication, flexibility is necessary when planning and conducting SVs. Future research recommendations include gathering student and clinician perceptions regarding faculty involvement in SVs, as well as gathering faculty perspectives regarding their participation in SVs. In addition, the impact of the pandemic on the future of SVs warrants further exploration.

Medical Students' Preferences on Practicing Intravenous Insertion on Each Other and Via Simulation.

SUMMARY STATEMENT: Medical students have traditionally practiced painful procedures such as intravenous (IV) line insertion on each other. Recently, there has been more emphasis on learning through simulation. Our study investigated students' attitudes regarding IV line insertion training, focusing on their anxiety, expectation to learn empathy, learning preference, and litigiousness. A 24-question survey was taken regarding anxiety and empathy when learning IV placement on each other versus on mannequins.Many students believed that they could learn empathy skills and better appreciate patient discomfort by learning IV placement through person-based practice. However, students who reported feeling anxious about having a student practice IV placement on them believed they were less likely to learn empathy through having a student practice IV insertion on them. The preferred method of learning painful procedures, such as IV placement, may be through a combination of simulation and person-based practice to mitigate anxiety while also enhancing empathy skills.

New aspects of redox signaling mediated by supersulfides in health and disease.

Oxygen molecules accept electrons from the respiratory chain in the mitochondria and are responsible for energy production in aerobic organisms. The reactive oxygen species formed via these oxygen reduction processes undergo complicated electron transfer reactions with other biological substances, which leads to alterations in their physiological functions and cause diverse biological and pathophysiological consequences (e.g., oxidative stress). Oxygen accounts for only a small proportion of the redox reactions in organisms, especially under aerobic or hypoxic conditions but not under anaerobic and hypoxic conditions. This article discusses a completely new concept of redox biology, which is governed by redox-active supersulfides, i.e., sulfur-catenated molecular species. These species are present in abundance in all organisms but remain largely unexplored in terms of redox biology and life science research. In fact, accumulating evidence shows that supersulfides have extensive redox chemical properties and that they can be readily ionized or radicalized to participate in energy metabolism, redox signaling, and oxidative stress responses in cells and in vivo. Thus, pharmacological intervention and medicinal modulation of supersulfide activities have been shown to benefit the regulation of disease pathogenesis as well as disease control.

2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels.

Reactive sulfane sulfur species such as persulfides (RSSH) and H2S2 are important redox regulators and closely linked to H2S signaling. However, the study of these species is still challenging due to their instability, high reactivity, and the lack of suitable donors to produce them. Herein we report a unique compound, 2H-thiopyran-2-thione sulfine (TTS), which can specifically convert H2S to HSOH, and then to H2S2 in the presence of excess H2S. Meanwhile, the reaction product 2H-thiopyran-2-thione (TT) can be oxidized to reform TTS by biological oxidants. The reaction mechanism of TTS is studied experimentally and computationally. TTS can be conjugated to proteins to achieve specific delivery, and the combination of TTS and H2S leads to highly efficient protein persulfidation. When TTS is applied in conjunction with established H2S donors, the corresponding donors of H2S2 (or its equivalents) are obtained. Cell-based studies reveal that TTS can effectively increase intracellular sulfane sulfur levels and compensate for certain aspects of sulfide:quinone oxidoreductase (SQR) deficiency. These properties make TTS a conceptually new strategy for the design of donors of reactive sulfane sulfur species.

Longevity control by supersulfide-mediated mitochondrial respiration and regulation of protein quality.

Supersulfides, which are defined as sulfur species with catenated sulfur atoms, are increasingly being investigated in biology. We recently identified pyridoxal phosphate (PLP)-dependent biosynthesis of cysteine persulfide (CysSSH) and related supersulfides by cysteinyl-tRNA synthetase (CARS). Here, we investigated the physiological role of CysSSH in budding yeast (Saccharomyces cerevisiae) by generating a PLP-binding site mutation K109A in CRS1 (the yeast ortholog of CARS), which decreased the synthesis of CysSSH and related supersulfides and also led to reduced chronological aging, effects that were associated with an increased endoplasmic reticulum stress response and impaired mitochondrial bioenergetics. Reduced chronological aging in the K109A mutant could be rescued by using exogenous supersulfide donors. Our findings indicate important roles for CARS in the production and metabolism of supersulfides-to mediate mitochondrial function and to regulate longevity.