Publications by authors named "Melanie R McReynolds"

15 Publications

  • Page 1 of 1

Mentoring during Uncertain Times.

Trends Biochem Sci 2021 Feb 20. Epub 2021 Feb 20.

Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Scientific success is mainly supported by mentoring, which often occurs through face-to-face interactions. Changes to the research environment incurred by the Coronavirus 2019 (COVID-19) pandemic have necessitated mentorship adaptations. Here, we describe how mentors can broaden their mentorship to support trainee growth and provide reassurance about trainee development amid uncertain circumstances.
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http://dx.doi.org/10.1016/j.tibs.2021.01.012DOI Listing
February 2021

Restoring metabolism of myeloid cells reverses cognitive decline in ageing.

Nature 2021 Feb 20;590(7844):122-128. Epub 2021 Jan 20.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease. Systemically, circulating pro-inflammatory factors can promote cognitive decline, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E (PGE), a major modulator of inflammation. In ageing macrophages and microglia, PGE signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.
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http://dx.doi.org/10.1038/s41586-020-03160-0DOI Listing
February 2021

The art of virtual mentoring in the twenty-first century for STEM majors and beyond.

Nat Biotechnol 2020 12;38(12):1477-1482

Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.

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http://dx.doi.org/10.1038/s41587-020-00758-7DOI Listing
December 2020

CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD and NMN levels.

Nat Metab 2020 11 16;2(11):1284-1304. Epub 2020 Nov 16.

Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.

Decreased NAD levels have been shown to contribute to metabolic dysfunction during aging. NAD decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38 immune cells. Inflammation increases CD38 and decreases NAD. In addition, senescent cells and their secreted signals promote accumulation of CD38 cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD.
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http://dx.doi.org/10.1038/s42255-020-00298-zDOI Listing
November 2020

Patching the Leaks: Revitalizing and Reimagining the STEM Pipeline.

Cell 2020 Oct;183(3):568-575

Department of Neurobiology, Harvard Medical School, Boston, MA. Electronic address:

We identify problematic areas throughout the Science, Technology, Engineering and Mathematics (STEM) pipeline that perpetuate racial disparities in academia. Distinct ways to curtail these disparities include early exposure and access to resources, supportive mentoring networks and comprehensive training programs specifically for racially minoritized students and trainees at each career stage. These actions will revitalize the STEM pipeline.
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http://dx.doi.org/10.1016/j.cell.2020.09.029DOI Listing
October 2020

Mentoring minority trainees: Minorities in academia face specific challenges that mentors should address to instill confidence.

EMBO Rep 2020 10 28;21(10):e51269. Epub 2020 Sep 28.

Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, NJ, USA.

A toolkit for mentoring minority students and trainees in science.
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http://dx.doi.org/10.15252/embr.202051269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534611PMC
October 2020

SLC25A51 is a mammalian mitochondrial NAD transporter.

Nature 2020 12 9;588(7836):174-179. Epub 2020 Sep 9.

Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Mitochondria require nicotinamide adenine dinucleotide (NAD) to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction. Mitochondrial NAD transporters have been identified in yeast and plants, but their existence in mammals remains controversial. Here we demonstrate that mammalian mitochondria can take up intact NAD, and identify SLC25A51 (also known as MCART1)-an essential mitochondrial protein of previously unknown function-as a mammalian mitochondrial NAD transporter. Loss of SLC25A51 decreases mitochondrial-but not whole-cell-NAD content, impairs mitochondrial respiration, and blocks the uptake of NAD into isolated mitochondria. Conversely, overexpression of SLC25A51 or SLC25A52 (a nearly identical paralogue of SLC25A51) increases mitochondrial NAD levels and restores NAD uptake into yeast mitochondria lacking endogenous NAD transporters. Together, these findings identify SLC25A51 as a mammalian transporter capable of importing NAD into mitochondria.
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http://dx.doi.org/10.1038/s41586-020-2741-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718333PMC
December 2020

Improved Annotation of Untargeted Metabolomics Data through Buffer Modifications That Shift Adduct Mass and Intensity.

Anal Chem 2020 09 12;92(17):11573-11581. Epub 2020 Aug 12.

Lewis Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States.

Annotation of untargeted high-resolution full-scan LC-MS metabolomics data remains challenging due to individual metabolites generating multiple LC-MS peaks arising from isotopes, adducts, and fragments. Adduct annotation is a particular challenge, as the same mass difference between peaks can arise from adduct formation, fragmentation, or different biological species. To address this, here we describe a buffer modification workflow (BMW) in which the same sample is run by LC-MS in both liquid chromatography solvent with NH-acetate buffer and in solvent with the buffer modified with NH-formate. Buffer switching results in characteristic mass and signal intensity changes for adduct peaks, facilitating their annotation. This relatively simple and convenient chromatography modification annotated yeast metabolomics data with similar effectiveness to growing the yeast in isotope-labeled media. Application to mouse liver data annotated both known metabolite and known adduct peaks with 95% accuracy. Overall, it identified 26% of ∼27 000 liver LC-MS features as putative metabolites, of which ∼2600 showed HMDB or KEGG database formula match. This workflow is well suited to biological samples that cannot be readily isotope labeled, including plants, mammalian tissues, and tumors.
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http://dx.doi.org/10.1021/acs.analchem.0c00985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484094PMC
September 2020

The power of saying no.

EMBO Rep 2020 07 28;21(7):e50918. Epub 2020 Jun 28.

Division of Hematology/Oncology, Department of Medicine, The University of California, Los Angeles, Los Angeles, CA, USA.

Many students and early-career scientists too often agree to new tasks and chores and end up overworked. Learning how and when to say "no" is therefore an important part of career development.
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http://dx.doi.org/10.15252/embr.202050918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332800PMC
July 2020

Serine Catabolism Feeds NADH when Respiration Is Impaired.

Cell Metab 2020 04 17;31(4):809-821.e6. Epub 2020 Mar 17.

Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address:

NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH-producing pathways: glucose, glutamine, and fat oxidation. Here, through deuterium-tracing studies in cultured cells and mice, we show that folate-dependent serine catabolism also produces substantial NADH. Strikingly, when respiration is impaired, serine catabolism through methylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source. In cells whose respiration is slowed by hypoxia, metformin, or genetic lesions, mitochondrial serine catabolism inhibition partially normalizes NADH levels and facilitates cell growth. In mice with engineered mitochondrial complex I deficiency (NDUSF4-/-), serine's contribution to NADH is elevated, and progression of spasticity is modestly slowed by pharmacological blockade of serine degradation. Thus, when respiration is impaired, serine catabolism contributes to toxic NADH accumulation.
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http://dx.doi.org/10.1016/j.cmet.2020.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397714PMC
April 2020

Age-related NAD decline.

Exp Gerontol 2020 Feb 22;134:110888. Epub 2020 Feb 22.

Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America. Electronic address:

Nicotinamide adenine dinucleotide (NAD) is an essential metabolite that is reported to decline in concentration in tissues of aged animals. Strategies to increase NAD availability have shown promise in treating many conditions in rodents, including age-related degeneration, which has in turn driven intense interest in the effects of supplements on human health. However, many aspects of NAD metabolism remain poorly understood, and human data are limited. Here, we discuss the state of the evidence for an age-related decline in NAD, along with potential mechanistic explanations, including increased consumption or decreased synthesis of NAD and changes in the composition of cells or tissues with age. Key challenges for the field involve the development of better tools to resolve information on the NAD content of specific cells and subcellular compartments as well as determining the threshold levels at which NAD depletion triggers physiological consequences in different tissues. Understanding how NAD metabolism changes with age in humans may ultimately allow the design of more targeted strategies to maintain its availability, such as inhibition of key consumers in specific tissues or direct delivery of precursors to sites of deficiency. In the meantime, human clinical trials with oral supplements are poised to provide some of the first direct evidence as to whether increasing NAD availability can impact human physiology. Thus, it is an exciting time for NAD research, with much remaining to be learned in terms of both basic biology and potential therapeutic applications.
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http://dx.doi.org/10.1016/j.exger.2020.110888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442590PMC
February 2020

Uridine monophosphate synthetase enables eukaryotic NAD biosynthesis from quinolinic acid.

J Biol Chem 2017 07 30;292(27):11147-11153. Epub 2017 May 30.

From the Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802

NAD biosynthesis is an attractive and promising therapeutic target for influencing health span and obesity-related phenotypes as well as tumor growth. Full and effective use of this target for therapeutic benefit requires a complete understanding of NAD biosynthetic pathways. Here, we report a previously unrecognized role for a conserved phosphoribosyltransferase in NAD biosynthesis. Because a required quinolinic acid phosphoribosyltransferase (QPRTase) is not encoded in its genome, are reported to lack a NAD biosynthetic pathway. However, all the genes of the kynurenine pathway required for quinolinic acid (QA) production from tryptophan are present. Thus, we investigated the presence of NAD biosynthesis in this organism. By combining isotope-tracing and genetic experiments, we have demonstrated the presence of an intact biosynthesis pathway for NAD from tryptophan via QA, highlighting the functional conservation of this important biosynthetic activity. Supplementation with kynurenine pathway intermediates also boosted NAD levels and partially reversed NAD-dependent phenotypes caused by mutation of , which encodes a nicotinamidase required for NAD salvage biosynthesis, demonstrating contribution of synthesis to NAD homeostasis. By investigating candidate phosphoribosyltransferase genes in the genome, we determined that the conserved uridine monophosphate phosphoribosyltransferase (UMPS), which acts in pyrimidine biosynthesis, is required for NAD biosynthesis in place of the missing QPRTase. We suggest that similar underground metabolic activity of UMPS may function in other organisms. This mechanism for NAD biosynthesis creates novel possibilities for manipulating NAD biosynthetic pathways, which is key for the future of therapeutics.
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http://dx.doi.org/10.1074/jbc.C117.795344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500784PMC
July 2017

Acoustofluidic Rotational Manipulation of Cells and Organisms Using Oscillating Solid Structures.

Small 2016 Oct 12;12(37):5120-5125. Epub 2016 Aug 12.

Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC, 27708, USA.

A polydimethylsiloxane microchannel featuring sidewall sharp-edge structures and bare channels, and a piezoelement transducer is attached to a thin glass slide. When an external acoustic field is applied to the microchannel, the oscillation of the sharp-edge structures and the thin glass slide generate acoustic streaming flows which in turn rotate single cells and C. elegans in-plane and out-of-plane.
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http://dx.doi.org/10.1002/smll.201601760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388358PMC
October 2016

Comparative Metabolomic Profiling Reveals That Dysregulated Glycolysis Stemming from Lack of Salvage NAD+ Biosynthesis Impairs Reproductive Development in Caenorhabditis elegans.

J Biol Chem 2015 Oct 8;290(43):26163-79. Epub 2015 Sep 8.

From the Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802 and

Temporal developmental progression is highly coordinated in Caenorhabditis elegans. However, loss of nicotinamidase PNC-1 activity slows reproductive development, uncoupling it from its typical progression relative to the soma. Using LC/MS we demonstrate that pnc-1 mutants do not salvage the nicotinamide released by NAD(+) consumers to resynthesize NAD(+), resulting in a reduction in global NAD(+) bioavailability. We manipulate NAD(+) levels to demonstrate that a minor deficit in NAD(+) availability is incompatible with a normal pace of gonad development. The NAD(+) deficit compromises NAD(+) consumer activity, but we surprisingly found no functional link between consumer activity and reproductive development. As a result we turned to a comparative metabolomics approach to identify the cause of the developmental phenotype. We reveal widespread metabolic perturbations, and using complementary pharmacological and genetic approaches, we demonstrate that a glycolytic block accounts for the slow pace of reproductive development. Interestingly, mitochondria are protected from both the deficiency in NAD(+) biosynthesis and the effects of reduced glycolytic output. We suggest that compensatory metabolic processes that maintain mitochondrial activity in the absence of efficient glycolysis are incompatible with the requirements for reproductive development, which requires high levels of cell division. In addition to demonstrating metabolic requirements for reproductive development, this work also has implications for understanding the mechanisms behind therapeutic interventions that target NAD(+) salvage biosynthesis for the purposes of inhibiting tumor growth.
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http://dx.doi.org/10.1074/jbc.M115.662916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646267PMC
October 2015

An NAD(+) biosynthetic pathway enzyme functions cell non-autonomously in C. elegans development.

Dev Dyn 2014 Aug 10;243(8):965-76. Epub 2014 May 10.

Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania.

Background: Disruption of cellular metabolite levels can adversely impact development. Specifically, loss-of-function of the C. elegans NAD(+) salvage biosynthesis gene PNC-1 results in an array of developmental phenotypes. Intriguingly, PNC-1 and its functional equivalent in vertebrates are secreted, but the contributions of the extracellular enzymes are poorly understood. We sought to study the tissue-specific requirements for PNC-1 expression and to examine the role of the secreted isoform.

Results: A thorough analysis of PNC-1 expression did not detect expression in tissues that require PNC-1 function. Limited expression of both the secreted and intracellular PNC-1 isoforms provided function at a distance from the tissues with phenotypes. We also find that the secreted isoform contributes to in vivo PNC-1 activity. Furthermore, uv1 cell survival has the most stringent requirements in terms of PNC-1 expression pattern or level.

Conclusions: Using careful promoter analysis and a restricted expression approach, we have shown that both the secreted and the intracellular PNC-1 isoforms function cell non-autonomously, and that the PNC-1a isoform is functionally relevant in vivo. Our work suggests a model where PNC-1 function is provided cell non-autonomously by a mix of intra and extracellular activity, most likely requiring NAD(+) salvage metabolite transport between tissues.
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http://dx.doi.org/10.1002/dvdy.24139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5245173PMC
August 2014