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51. Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation

Author

CMM Groep Coffer, Cancer, Infection & Immunity, CMM Groep Burgering, CMM Groep Van Mil, CTI Radstake, CTI Research, Immuno/reuma onderzoek 3 (Loosdregt), Child Health, CDL Onderzoek Pasterkamp, Experimentele Afd. Cardiologie 1, Circulatory Health, CMM Sectie Molecular Cancer Research, CMM Sectie Stem Cells, Onderzoek, Regenerative Medicine and Stem Cells, Mocholi, Enric, Russo, Laura, Gopal, Keshav, Ramstead, Andrew G, Hochrein, Sophia M, Vos, Harmjan R, Geeven, Geert, Adegoke, Adeolu O, Hoekstra, Anna, van Es, Robert M, Pittol, Jose Ramos, Vastert, Sebastian, Rutter, Jared, Radstake, Timothy, van Loosdregt, Jorg, Berkers, Celia, Mokry, Michal, Anderson, Colin C, O'Connell, Ryan M, Vaeth, Martin, Ussher, John, Burgering, Boudewijn M T, Coffer, Paul J, CMM Groep Coffer, Cancer, Infection & Immunity, CMM Groep Burgering, CMM Groep Van Mil, CTI Radstake, CTI Research, Immuno/reuma onderzoek 3 (Loosdregt), Child Health, CDL Onderzoek Pasterkamp, Experimentele Afd. Cardiologie 1, Circulatory Health, CMM Sectie Molecular Cancer Research, CMM Sectie Stem Cells, Onderzoek, Regenerative Medicine and Stem Cells, Mocholi, Enric, Russo, Laura, Gopal, Keshav, Ramstead, Andrew G, Hochrein, Sophia M, Vos, Harmjan R, Geeven, Geert, Adegoke, Adeolu O, Hoekstra, Anna, van Es, Robert M, Pittol, Jose Ramos, Vastert, Sebastian, Rutter, Jared, Radstake, Timothy, van Loosdregt, Jorg, Berkers, Celia, Mokry, Michal, Anderson, Colin C, O'Connell, Ryan M, Vaeth, Martin, Ussher, John, Burgering, Boudewijn M T, and Coffer, Paul J

Published
2023

52. Evidence of Glycolysis Up-Regulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning

Author

Diakos, Nikolaos A., Navankasattusas, Sutip, Abel, E. Dale, Rutter, Jared, McCreath, Lauren, Ferrin, Peter, McKellar, Stephen H., Miller, Dylan V., Park, Song Y., Richardson, Russell S., Deberardinis, Ralph, Cox, James E., Kfoury, Abdallah G., Selzman, Craig H., Stehlik, Josef, Fang, James C., Li, Dean Y., and Drakos, Stavros G.

Published
2016
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53. Author response: Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency

Author

Webb, Bryn D, primary, Nowinski, Sara M, primary, Solmonson, Ashley, additional, Ganesh, Jaya, additional, Rodenburg, Richard J, additional, Leandro, Joao, additional, Evans, Anthony, additional, Vu, Hieu S, additional, Naidich, Thomas P, additional, Gelb, Bruce D, additional, DeBerardinis, Ralph J, additional, Rutter, Jared, additional, and Houten, Sander M, additional

Published
2023
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54. Hepatic Mitochondrial Pyruvate Carrier 1 Is Required for Efficient Regulation of Gluconeogenesis and Whole-Body Glucose Homeostasis

Author

Gray, Lawrence R., Sultana, Mst Rasheda, Rauckhorst, Adam J., Oonthonpan, Lalita, Tompkins, Sean C., Sharma, Arpit, Fu, Xiaorong, Miao, Ren, Pewa, Alvin D., Brown, Kathryn S., Lane, Erin E., Dohlman, Ashley, Zepeda-Orozco, Diana, Xie, Jianxin, Rutter, Jared, Norris, Andrew W., Cox, James E., Burgess, Shawn C., Potthoff, Matthew J., and Taylor, Eric B.

Published
2015
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56. Recessive pathogenic variants inMCATcause combined oxidative phosphorylation deficiency

Author

Webb, Bryn D., primary, Nowinski, Sara M., additional, Solmonson, Ashley, additional, Ganesh, Jaya, additional, Rodenburg, Richard J., additional, Leandro, João, additional, Evans, Anthony, additional, Vu, Hieu S., additional, Naidich, Thomas P., additional, Gelb, Bruce D., additional, DeBerardinis, Ralph J., additional, Rutter, Jared, additional, and Houten, Sander M., additional

Published
2022
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57. Publisher Correction: Mitochondrial pyruvate carriers are required for myocardial stress adaptation

Author

Zhang, Yuan, Taufalele, Paul V., Cochran, Jesse D., Robillard-Frayne, Isabelle, Marx, Jonas Maximilian, Soto, Jamie, Rauckhorst, Adam J., Tayyari, Fariba, Pewa, Alvin D., Gray, Lawrence R., Teesch, Lynn M., Puchalska, Patrycja, Funari, Trevor R., McGlauflin, Rose, Zimmerman, Kathy, Kutschke, William J., Cassier, Thomas, Hitchcock, Shannon, Lin, Kevin, Kato, Kevin M., Stueve, Jennifer L., Haff, Lauren, Weiss, Robert M., Cox, James E., Rutter, Jared, Taylor, Eric B., Crawford, Peter A., Lewandowski, E. Douglas, Des Rosiers, Christine, and Abel, E. Dale

Published
2020
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58. Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction

Author

Winter, Jacob M, primary, Fresenius, Heidi L, additional, Cunningham, Corey N, additional, Wei, Peng, additional, Keys, Heather R, additional, Berg, Jordan, additional, Bott, Alex, additional, Yadav, Tarun, additional, Ryan, Jeremy, additional, Sirohi, Deepika, additional, Tripp, Sheryl R, additional, Barta, Paige, additional, Agarwal, Neeraj, additional, Letai, Anthony, additional, Sabatini, David M, additional, Wohlever, Matthew L, additional, and Rutter, Jared, additional

Published
2022
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59. Author response: Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction

Author

Winter, Jacob M, primary, Fresenius, Heidi L, additional, Cunningham, Corey N, additional, Wei, Peng, additional, Keys, Heather R, additional, Berg, Jordan, additional, Bott, Alex, additional, Yadav, Tarun, additional, Ryan, Jeremy, additional, Sirohi, Deepika, additional, Tripp, Sheryl R, additional, Barta, Paige, additional, Agarwal, Neeraj, additional, Letai, Anthony, additional, Sabatini, David M, additional, Wohlever, Matthew L, additional, and Rutter, Jared, additional

Published
2022
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60. Intramuscular administration of glyoxylate rescues swine from lethal cyanide poisoning and ameliorates the biochemical sequalae of cyanide intoxication

Author

Bebarta, Vik S, primary, Shi, Xu, additional, Zheng, Shunning, additional, Hendry-Hofer, Tara B, additional, Severance, Carter C, additional, Behymer, Matthew M, additional, Boss, Gerry R, additional, Mahon, Sari, additional, Brenner, Matthew, additional, Knipp, Gregory T, additional, Davisson, Vincent Jo, additional, Peterson, Randall T, additional, MacRae, Calum A, additional, Rutter, Jared, additional, Gerszten, Robert E, additional, and Nath, Anjali K, additional

Published
2022
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61. Phosphatidylethanolamine facilitates mitochondrial pyruvate entry to regulate metabolic flexibility

Author

Siripoksup, Piyarat, primary, Cao, Guoshen, additional, Cluntun, Ahmad A., additional, Maschek, J. Alan, additional, Pearce, Quentinn, additional, Lang, Marisa J., additional, Eshima, Hiroaki, additional, Opurum, Precious C., additional, Mahmassani, Ziad S., additional, Taylor, Eric B., additional, Cox, James E., additional, Drummond, Micah J., additional, Rutter, Jared, additional, and Funai, Katsuhiko, additional

Published
2022
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62. Phosphate Starvation Signaling Increases Mitochondrial Membrane Potential through Respiration-independent Mechanisms

Author

Ouyang, Yeyun, primary, Cunningham, Corey N., additional, Berg, Jordan A., additional, Toshniwal, Ashish G., additional, Hughes, Casey E., additional, Van Vranken, Jonathan G., additional, Jeong, Mi-Young, additional, Cluntun, Ahmad A., additional, Lam, Geanette, additional, Winter, Jacob M., additional, Akdoǧan, Emel, additional, Dove, Katja K., additional, Gygi, Steven P., additional, Dunn, Cory D, additional, Winge, Dennis R, additional, and Rutter, Jared, additional

Published
2022
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63. Mitochondrial pyruvate supports lymphoma proliferation by fueling a glutamate pyruvate transaminase 2–dependent glutaminolysis pathway

Author

Wei, Peng, primary, Bott, Alex J., additional, Cluntun, Ahmad A., additional, Morgan, Jeffrey T., additional, Cunningham, Corey N., additional, Schell, John C., additional, Ouyang, Yeyun, additional, Ficarro, Scott B., additional, Marto, Jarrod A., additional, Danial, Nika N., additional, DeBerardinis, Ralph J., additional, and Rutter, Jared, additional

Published
2022
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69. Mitochondrial Phosphatidylethanolamine Directly Regulates UCP1 to Promote Brown Adipose Thermogenesis

Author

Johnson, Jordan M., primary, Peterlin, Alek D., additional, Balderas, Enrique, additional, Sustarsic, Elahu G., additional, Maschek, J. Alan, additional, Lang, Marisa J., additional, Jara-Ramos, Alejandro, additional, Panic, Vanja, additional, Morgan, Jeffrey T., additional, Villanueva, Claudio J., additional, Sanchez, Alejandro, additional, Rutter, Jared, additional, Lodhi, Irfan J., additional, Cox, James E., additional, Fisher-Wellman, Kelsey H., additional, Chaudhuri, Dipayan, additional, Gerhart-Hines, Zachary, additional, and Funai, Katsuhiko, additional

Published
2022
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71. Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency

Author

Ministerio de Economía y Competitividad (España), Swiss National Science Foundation, De La Rossa, Andrés, Laporte,Marine H., Astori, Simone, Marissal, Thomas, Montessuit, Sylvie, Sheshadri, Preethi, Ramos-Fernández, Eva, Méndez, Pablo, Khani, Abbas, Quairiaux, Charles, Taylor, Eric B., Rutter, Jared, Nunes, José Manuel, Carleton, Alan, Duchen, Michel R., Sandi, Carmen, Martinou, Jean-Claude, Ministerio de Economía y Competitividad (España), Swiss National Science Foundation, De La Rossa, Andrés, Laporte,Marine H., Astori, Simone, Marissal, Thomas, Montessuit, Sylvie, Sheshadri, Preethi, Ramos-Fernández, Eva, Méndez, Pablo, Khani, Abbas, Quairiaux, Charles, Taylor, Eric B., Rutter, Jared, Nunes, José Manuel, Carleton, Alan, Duchen, Michel R., Sandi, Carmen, and Martinou, Jean-Claude

Abstract

Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the MPC, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation and decreased mitochondrial membrane potential in these excitatory neurons, mice were normal at rest. Surprisingly, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behavior of control mice remained unchanged. We report that neurons with a deficient MPC were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced M-type potassium channel activity. Provision of ketone bodies restored energy status, calcium homeostasis and M-channel activity and attenuated seizures in animals fed a ketogenic diet. Our results provide an explanation for the seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit.

Published
2022

77. Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency

Author

De La Rossa, Andres, primary, Laporte, Marine H, primary, Astori, Simone, primary, Marissal, Thomas, additional, Montessuit, Sylvie, additional, Sheshadri, Preethi, additional, Ramos-Fernández, Eva, additional, Mendez, Pablo, additional, Khani, Abbas, additional, Quairiaux, Charles, additional, Taylor, Eric B, additional, Rutter, Jared, additional, Nunes, José Manuel, additional, Carleton, Alan, additional, Duchen, Michael R, additional, Sandi, Carmen, additional, and Martinou, Jean-Claude, additional

Published
2022
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78. Pyruvate metabolism controls epigenome remodeling during CD4+ T cell activation

Author

Mocholi, Enric, primary, Russo, Laura, additional, Gopal, Keshav, additional, Ramstead, Andrew, additional, Hochrein, Sophia M., additional, Vos, HarmJan, additional, Geeven, Geert, additional, Adegoke, Adeolu, additional, Hoekstra, Anna, additional, Es, Robert van, additional, Pittol, José Ramos, additional, Vastert, Sebastiaan, additional, Rutter, Jared, additional, Radstake, Timothy, additional, Loosdregt, Jorg van, additional, Berkers, Celia, additional, Mokry, Michal, additional, Anderson, Colin, additional, O'Connell, Ryan, additional, Vaeth, Martin, additional, Ussher, John, additional, Burgering, Boudewijn, additional, and Coffer, Paul, additional

Published
2022
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79. Author response: Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency

Author

De La Rossa, Andres, primary, Laporte, Marine H, primary, Astori, Simone, primary, Marissal, Thomas, additional, Montessuit, Sylvie, additional, Sheshadri, Preethi, additional, Ramos-Fernández, Eva, additional, Mendez, Pablo, additional, Khani, Abbas, additional, Quairiaux, Charles, additional, Taylor, Eric B, additional, Rutter, Jared, additional, Nunes, José Manuel, additional, Carleton, Alan, additional, Duchen, Michael R, additional, Sandi, Carmen, additional, and Martinou, Jean-Claude, additional

Published
2022
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85. Protein-Metabolite Interactomics Reveals Novel Regulation of Carbohydrate Metabolism

Author

Hicks, Kevin G., primary, Cluntun, Ahmad A., additional, Schubert, Heidi L., additional, Hackett, Sean R., additional, Berg, Jordan A., additional, Leonard, Paul G., additional, Ajalla Aleixo, Mariana A., additional, Blevins, Aubrie, additional, Barta, Paige, additional, Tilley, Samantha, additional, Fogarty, Sarah, additional, Winter, Jacob M., additional, Ahn, Hee-Chul, additional, Allen, Karen N., additional, Block, Samuel, additional, Cardoso, Iara A., additional, Ding, Jianping, additional, Dreveny, Ingrid, additional, Gasper, Clarke, additional, Ho, Quinn, additional, Matsuura, Atsushi, additional, Palladino, Michael J., additional, Prajapati, Sabin, additional, Sun, PengKai, additional, Tittmann, Kai, additional, Tolan, Dean R., additional, Unterlass, Judith, additional, VanDemark, Andrew P., additional, Vander Heiden, Matthew G., additional, Webb, Bradley A., additional, Yun, Cai-Hong, additional, Zhap, PengKai, additional, Hill, Christopher P., additional, Nonato, Maria Cristina, additional, Muller, Florian L., additional, Gottschling, Daniel E., additional, Cox, James E., additional, and Rutter, Jared, additional

Published
2021
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86. Mitochondrial pyruvate supports lymphoma proliferation by fueling a non-canonical glutamine metabolism pathway

Author

Wei, Peng, primary, Bott, Alex J., additional, Cluntun, Ahmad A., additional, Morgan, Jeffrey T., additional, Cunningham, Corey N., additional, Schell, John C., additional, Ouyang, Yeyun, additional, Ficarro, Scott B., additional, Marto, Jarrod A., additional, Danial, Nika N., additional, DeBerardinis, Ralph J., additional, and Rutter, Jared, additional

Published
2021
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88. Metabolic decisions in development and disease—a Keystone Symposia report

Author

Cable, Jennifer, primary, Pourquié, Olivier, additional, Wellen, Kathryn E., additional, Finley, Lydia W. S., additional, Aulehla, Alexander, additional, Gould, Alex P., additional, Teleman, Aurelio, additional, Tu, William B., additional, Garrett, Wendy Sarah, additional, Miguel‐Aliaga, Irene, additional, Perrimon, Norbert, additional, Hooper, Lora V., additional, Walhout, A. J. Marian, additional, Wei, Wei, additional, Alexandrov, Theodore, additional, Erez, Ayelet, additional, Ralser, Markus, additional, Rabinowitz, Joshua D., additional, Hemalatha, Anupama, additional, Gutiérrez‐Pérez, Paula, additional, Chandel, Navdeep S., additional, Rutter, Jared, additional, Locasale, Jason W., additional, Landoni, Juan C., additional, and Christofk, Heather, additional

Published
2021
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90. The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder

Author

Nuebel, Esther, primary, Morgan, Jeffrey T, additional, Fogarty, Sarah, additional, Winter, Jacob M, additional, Lettlova, Sandra, additional, Berg, Jordan A, additional, Chen, Yu‐Chan, additional, Kidwell, Chelsea U, additional, Maschek, J Alan, additional, Clowers, Katie J, additional, Argyriou, Catherine, additional, Chen, Lingxiao, additional, Wittig, Ilka, additional, Cox, James E, additional, Roh‐Johnson, Minna, additional, Braverman, Nancy, additional, Bonkowsky, Joshua, additional, Gygi, Steven P, additional, and Rutter, Jared, additional

Published
2021
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91. Co-deletion of ATAD1 with PTEN primes cells for BIM-mediated apoptosis

Author

Winter, Jacob M., primary, Fresenius, Heidi L., additional, Keys, Heather R., additional, Cunningham, Corey N., additional, Ryan, Jeremy, additional, Sirohi, Deepika, additional, Berg, Jordan A., additional, Tripp, Sheryl R., additional, Barta, Paige, additional, Agarwal, Neeraj, additional, Letai, Anthony, additional, Sabatini, David M., additional, Wohlever, Matthew L., additional, and Rutter, Jared, additional

Published
2021
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92. Protective mitochondrial fission induced by stress-responsive protein GJA1-20k

Author

Shimura, Daisuke, Nuebel, Esther, Baum, Rachel, Valdez, Steven E., Xiao, Shaohua, Warren, Junco S., Palatinus, Joseph A., Hong, TingTing, Rutter, Jared, Shaw, Robin M., Shimura, Daisuke, Nuebel, Esther, Baum, Rachel, Valdez, Steven E., Xiao, Shaohua, Warren, Junco S., Palatinus, Joseph A., Hong, TingTing, Rutter, Jared, and Shaw, Robin M.

Abstract

The Connexin43 gap junction gene GJA1 has one coding exon, but its mRNA undergoes internal translation to generate N-terminal truncated isoforms of Connexin43 with the predominant isoform being only 20 kDa in size (GJA1-20k). Endogenous GJA1-20k protein is not membrane bound and has been found to increase in response to ischemic stress, localize to mitochondria, and mimic ischemic preconditioning protection in the heart. However, it is not known how GJA1-20k benefits mitochondria to provide this protection. Here, using human cells and mice, we identify that GJA1-20k polymerizes actin around mitochondria which induces focal constriction sites. Mitochondrial fission events occur within about 45 s of GJA1-20k recruitment of actin. Interestingly, GJA1-20k mediated fission is independent of canonical Dynamin-Related Protein 1 (DRP1). We find that GJA1-20k-induced smaller mitochondria have decreased reactive oxygen species (ROS) generation and, in hearts, provide potent protection against ischemia-reperfusion injury. The results indicate that stress responsive internally translated GJA1-20k stabilizes polymerized actin filaments to stimulate non-canonical mitochondrial fission which limits ischemic-reperfusion induced myocardial infarction.

Published
2021

93. Identification of small molecule allosteric modulators of 5,10-methylenetetrahydrofolate reductase (MTHFR) by targeting its unique regulatory domain

Author

Bezerra, Gustavo A, Holenstein, Alexander, Foster, William R, Xie, Bing, Hicks, Kevin G, Bürer, Céline, Lutz, Seraina, Mukherjee, Ayan, Sarkar, Dipika, Bhattacharya, Debomita, Rutter, Jared, Talukdar, Arindam, Brown, Peter J, Luo, Minkui, Shi, Lei, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, Yue, Wyatt W; https://orcid.org/0000-0001-6959-6007, Bezerra, Gustavo A, Holenstein, Alexander, Foster, William R, Xie, Bing, Hicks, Kevin G, Bürer, Céline, Lutz, Seraina, Mukherjee, Ayan, Sarkar, Dipika, Bhattacharya, Debomita, Rutter, Jared, Talukdar, Arindam, Brown, Peter J, Luo, Minkui, Shi, Lei, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, and Yue, Wyatt W; https://orcid.org/0000-0001-6959-6007

Abstract

The folate and methionine cycles, constituting one-carbon metabolism, are critical pathways for cell survival. Intersecting these two cycles, 5,10-methylenetetrahydrofolate reductase (MTHFR) directs one-carbon units from the folate to methionine cycle, to be exclusively used for methionine and S-adenosylmethionine (AdoMet) synthesis. MTHFR deficiency and upregulation result in diverse disease states, rendering it an attractive drug target. The activity of MTHFR is inhibited by the binding of AdoMet to an allosteric regulatory domain distal to the enzyme’s active site, which we have previously identified to constitute a novel fold with a druggable pocket. Here, we screened 162 AdoMet mimetics using differential scanning fluorimetry, and identified 4 compounds that stabilized this regulatory domain. Three compounds were sinefungin analogues, closely related to AdoMet and S-adenosylhomocysteine (AdoHcy). The strongest thermal stabilisation was provided by (S)-SKI-72, a potent inhibitor originally developed for protein arginine methyltransferase 4 (PRMT4). Using surface plasmon resonance, we confirmed that (S)-SKI-72 binds MTHFR via its allosteric domain with nanomolar affinity. Assay of MTHFR activity in the presence of (S)-SKI-72 demonstrates inhibition of purified enzyme with sub-micromolar potency and endogenous MTHFR from HEK293 cell lysate in the low micromolar range, both of which are lower than AdoMet. Nevertheless, unlike AdoMet, (S)-SKI-72 is unable to completely abolish MTHFR activity, even at very high concentrations. Combining binding assays, kinetic characterization and compound docking, this work indicates the regulatory domain of MTHFR can be targeted by small molecules and presents (S)-SKI-72 as an excellent candidate for development of MTHFR inhibitors.

Published
2021

94. Author Reply to Peer Reviews of Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency

Author

Martinou, Jean-Claude, primary, Sandi, Carmen, additional, Duchen, Michael R., additional, Carleton, Alan, additional, Nunes, José Manuel, additional, Rutter, Jared, additional, Taylor, Eric, additional, Quairiaux, Charles, additional, Khani, Abbas, additional, Mendez, Pablo, additional, Ramos-Fernández, Eva, additional, Sheshadri, Preethi, additional, Montessuit, Sylvie, additional, Marissal, Thomas, additional, Astori, Simone, additional, Laporte, Marine H., additional, and De la Rossa, Andres, additional

Published
2021
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96. Identification of small molecule allosteric modulators of 5,10-methylenetetrahydrofolate reductase (MTHFR) by targeting its unique regulatory domain

Author

Bezerra, Gustavo A., primary, Holenstein, Alexander, additional, Foster, William R., additional, Xie, Bing, additional, Hicks, Kevin G., additional, Bürer, Céline, additional, Lutz, Seraina, additional, Mukherjee, Ayan, additional, Sarkar, Dipika, additional, Bhattacharya, Debomita, additional, Rutter, Jared, additional, Talukdar, Arindam, additional, Brown, Peter J., additional, Luo, Minkui, additional, Shi, Lei, additional, Froese, D. Sean, additional, and Yue, Wyatt W., additional

Published
2021
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98. T Cell-Expressed microRNA-155 Reduces Lifespan in a Mouse Model of Age-Related Chronic Inflammation

Author

Ekiz, H Atakan, Ramstead, Andrew G, Lee, Soh-Hyun, Nelson, Morgan C, Bauer, Kaylyn M, Wallace, Jared A, Hu, Ruozhen, Round, June L, Rutter, Jared, Drummond, Micah J, Rao, Dinesh S, and O'Connell, Ryan M

Subjects
Inflammation, Male, Animal, T-Lymphocytes, Knockout, Longevity, Immunology, Age Factors, Inbred C57BL, Transgenic, Mice, MicroRNAs, Disease Models, Animals, Female
Abstract

Aging-related chronic inflammation is a risk factor for many human disorders through incompletely understood mechanisms. Aged mice deficient in microRNA (miRNA/miR)-146a succumb to life-shortening chronic inflammation. In this study, we report that miR-155 in T cells contributes to shortened lifespan of miR-146a-/- mice. Using single-cell RNA sequencing and flow cytometry, we found that miR-155 promotes the activation of effector T cell populations, including T follicular helper cells, and increases germinal center B cells and autoantibodies in mice aged over 15 months. Mechanistically, aerobic glycolysis genes are elevated in T cells during aging, and upon deletion of miR-146a, in a T cell miR-155-dependent manner. Finally, skewing T cell metabolism toward aerobic glycolysis by deleting mitochondrial pyruvate carrier recapitulates age-dependent T cell phenotypes observed in miR-146a-/- mice, revealing the sufficiency of metabolic reprogramming to influence immune cell functions during aging. Altogether, these data indicate that T cell-specific miRNAs play pivotal roles in regulating lifespan through their influences on inflammaging.

Published
2020

100. A Non-Canonical Convergence of Carbohydrate and Glutamine Metabolism is Required After Metabolic Rewiring in a Solid Environment

Author

Wei, Peng, primary, Bott, Alex J., additional, Cluntun, Ahmad, additional, Morgan, Jeff, additional, Cunningham, Corey N., additional, Schell, John C., additional, Ouyang, Yeyun, additional, Ficarro, Scott B., additional, Marto, Jarrod A., additional, Danial, Nika N., additional, DeBerardinis, Ralph J., additional, and Rutter, Jared, additional

Published
2021
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