Search

Your search keyword '"Parkhitko, Andrey A."' showing total 139 results
Start Over Author "Parkhitko, Andrey A."
139 results on '"Parkhitko, Andrey A."'

2. ARDD 2020: from aging mechanisms to interventions

Author

Mkrtchyan, Garik V, Abdelmohsen, Kotb, Andreux, Pénélope, Bagdonaite, Ieva, Barzilai, Nir, Brunak, Søren, Cabreiro, Filipe, de Cabo, Rafael, Campisi, Judith, Cuervo, Ana Maria, Demaria, Marco, Ewald, Collin Y, Fang, Evandro Fei, Faragher, Richard, Ferrucci, Luigi, Freund, Adam, Silva-García, Carlos G, Georgievskaya, Anastasia, Gladyshev, Vadim N, Glass, David J, Gorbunova, Vera, de Grey, Aubrey, He, Wei-Wu, Hoeijmakers, Jan, Hoffmann, Eva, Horvath, Steve, Houtkooper, Riekelt H, Jensen, Majken K, Jensen, Martin Borch, Kane, Alice, Kassem, Moustapha, de Keizer, Peter, Kennedy, Brian, Karsenty, Gerard, Lamming, Dudley W, Lee, Kai-Fu, MacAulay, Nanna, Mamoshina, Polina, Mellon, Jim, Molenaars, Marte, Moskalev, Alexey, Mund, Andreas, Niedernhofer, Laura, Osborne, Brenna, Pak, Heidi H, Parkhitko, Andrey, Raimundo, Nuno, Rando, Thomas A, Rasmussen, Lene Juel, Reis, Carolina, Riedel, Christian G, Franco-Romero, Anais, Schumacher, Björn, Sinclair, David A, Suh, Yousin, Taub, Pam R, Toiber, Debra, Treebak, Jonas T, Valenzano, Dario Riccardo, Verdin, Eric, Vijg, Jan, Young, Sergey, Zhang, Lei, Bakula, Daniela, Zhavoronkov, Alex, and Scheibye-Knudsen, Morten

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Clinical Sciences, Biological Sciences, Aging, Good Health and Well Being, Artificial Intelligence, Biomedical Research, Cellular Senescence, Congresses as Topic, Drug Discovery, Humans, Life Style, Longevity, Pharmaceutical Preparations, aging, interventions, drug discovery, artificial intelligence, Biochemistry and cell biology, Clinical sciences
Abstract

Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8th ARDD meeting that is scheduled for the 31st of August to 3rd of September, 2021, at Columbia University, USA.

Published
2020

4. Unique tau‐ and synuclein‐dependent metabolic reprogramming in neurons distinct from normal aging.

Author

Yadav, Shweta, Graham, Aidan, Al Hammood, Farazdaq, Garbark, Chris, Vasudevan, Deepika, Pandey, Udai, Asara, John M., Rajasundaram, Dhivyaa, and Parkhitko, Andrey A.

Subjects
METABOLIC reprogramming, PARKINSON'S disease, ALZHEIMER'S disease, PATHOLOGY, DROSOPHILA
Abstract

Neuronal cells are highly specialized cells and have a specific metabolic profile to support their function. It has been demonstrated that the metabolic profiles of different cells/tissues undergo significant reprogramming with advancing age, which has often been considered a contributing factor towards aging‐related diseases including Alzheimer's (AD) and Parkinson's (PD) diseases. However, it is unclear if the metabolic changes associated with normal aging predispose neurons to disease conditions or a distinct set of metabolic alterations happen in neurons in AD or PD which might contribute to disease pathologies. To decipher the changes in neuronal metabolism with age, in AD, or in PD, we performed high‐throughput steady‐state metabolite profiling on heads in wildtype Drosophila and in Drosophila models relevant to AD and PD. Intriguingly, we found that the spectrum of affected metabolic pathways is dramatically different between normal aging, Tau, or Synuclein overexpressing neurons. Genetic targeting of the purine and glutamate metabolism pathways, which were dysregulated in both old age and disease conditions partially rescued the neurodegenerative phenotype associated with the overexpression of wildtype and mutant tau. Our findings support a "two‐hit model" to explain the pathological manifestations associated with AD where both aging‐ and Tau/Synuclein‐ driven metabolic reprogramming events cooperate with each other, and targeting both could be a potent therapeutic strategy. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

7. Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes

Author

Rodriguez-Muela, Natalia, Parkhitko, Andrey, Grass, Tobias, Gibbs, Rebecca M., Norabuena, Erika M., Perrimon, Norbert, Singh, Rajat, and Rubin, Lee L.

Subjects
Physiological aspects, Research, Genetic aspects, Risk factors, Motor neurons -- Research -- Physiological aspects -- Genetic aspects, Spinal muscular atrophy -- Care and treatment -- Research -- Risk factors -- Genetic aspects, Gene mutation -- Research, Binding proteins -- Research -- Physiological aspects
Abstract

Introduction Spinal muscular atrophy (SMA) is an early-onset, autosomal recessive neuromuscular disease caused by low levels of survival motor neuron (SMN) protein (1). SMA is primarily characterized by the degeneration [...], Spinal muscular atrophy (SMA), a degenerative motor neuron (MN) disease, caused by loss of functional survival of motor neuron (SMN) protein due to SMN1 gene mutations, is a leading cause of infant mortality. Increasing SMN levels ameliorates the disease phenotype and is unanimously accepted as a therapeutic approach for patients with SMA. The ubiquitin/proteasome system is known to regulate SMN protein levels; however, whether autophagy controls SMN levels remains poorly explored. Here, we show that SMN protein is degraded by autophagy. Pharmacological and genetic inhibition of autophagy increases SMN levels, while induction of autophagy decreases these levels. SMN degradation occurs via its interaction with the autophagy adapter p62 (also known as SQSTM1). We also show that SMA neurons display reduced autophagosome clearance, increased p62 and ubiquitinated proteins levels, and hyperactivated mTORC1 signaling. Importantly, reducing p62 levels markedly increases SMN and its binding partner gemin2, promotes MN survival, and extends lifespan in fly and mouse SMA models, revealing p62 as a potential new therapeutic target for the treatment of SMA.

Published
2018
Full Text
View/download PDF

8. Supplementary Figure 4 from Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Author

Parkhitko, Andrey A., primary, Priolo, Carmen, primary, Coloff, Jonathan L., primary, Yun, Jihye, primary, Wu, Julia J., primary, Mizumura, Kenji, primary, Xu, Wenping, primary, Malinowska, Izabela A., primary, Yu, Jane, primary, Kwiatkowski, David J., primary, Locasale, Jason W., primary, Asara, John M., primary, Choi, Augustine M.K., primary, Finkel, Toren, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

9. Supplementary Figure 3 from Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Author

Parkhitko, Andrey A., primary, Priolo, Carmen, primary, Coloff, Jonathan L., primary, Yun, Jihye, primary, Wu, Julia J., primary, Mizumura, Kenji, primary, Xu, Wenping, primary, Malinowska, Izabela A., primary, Yu, Jane, primary, Kwiatkowski, David J., primary, Locasale, Jason W., primary, Asara, John M., primary, Choi, Augustine M.K., primary, Finkel, Toren, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

10. Supplementary Table 1 from Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Author

Parkhitko, Andrey A., primary, Priolo, Carmen, primary, Coloff, Jonathan L., primary, Yun, Jihye, primary, Wu, Julia J., primary, Mizumura, Kenji, primary, Xu, Wenping, primary, Malinowska, Izabela A., primary, Yu, Jane, primary, Kwiatkowski, David J., primary, Locasale, Jason W., primary, Asara, John M., primary, Choi, Augustine M.K., primary, Finkel, Toren, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

11. Data from Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Author

Parkhitko, Andrey A., primary, Priolo, Carmen, primary, Coloff, Jonathan L., primary, Yun, Jihye, primary, Wu, Julia J., primary, Mizumura, Kenji, primary, Xu, Wenping, primary, Malinowska, Izabela A., primary, Yu, Jane, primary, Kwiatkowski, David J., primary, Locasale, Jason W., primary, Asara, John M., primary, Choi, Augustine M.K., primary, Finkel, Toren, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

13. Supplementary Figure 8 from Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Author

Parkhitko, Andrey A., primary, Priolo, Carmen, primary, Coloff, Jonathan L., primary, Yun, Jihye, primary, Wu, Julia J., primary, Mizumura, Kenji, primary, Xu, Wenping, primary, Malinowska, Izabela A., primary, Yu, Jane, primary, Kwiatkowski, David J., primary, Locasale, Jason W., primary, Asara, John M., primary, Choi, Augustine M.K., primary, Finkel, Toren, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

15. Supplementary Figure 5 from Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Author

Parkhitko, Andrey A., primary, Priolo, Carmen, primary, Coloff, Jonathan L., primary, Yun, Jihye, primary, Wu, Julia J., primary, Mizumura, Kenji, primary, Xu, Wenping, primary, Malinowska, Izabela A., primary, Yu, Jane, primary, Kwiatkowski, David J., primary, Locasale, Jason W., primary, Asara, John M., primary, Choi, Augustine M.K., primary, Finkel, Toren, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

16. Supplementary Figure Legend from Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Author

Parkhitko, Andrey A., primary, Priolo, Carmen, primary, Coloff, Jonathan L., primary, Yun, Jihye, primary, Wu, Julia J., primary, Mizumura, Kenji, primary, Xu, Wenping, primary, Malinowska, Izabela A., primary, Yu, Jane, primary, Kwiatkowski, David J., primary, Locasale, Jason W., primary, Asara, John M., primary, Choi, Augustine M.K., primary, Finkel, Toren, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

17. Supplementary Figure 2 from Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Author

Parkhitko, Andrey A., primary, Priolo, Carmen, primary, Coloff, Jonathan L., primary, Yun, Jihye, primary, Wu, Julia J., primary, Mizumura, Kenji, primary, Xu, Wenping, primary, Malinowska, Izabela A., primary, Yu, Jane, primary, Kwiatkowski, David J., primary, Locasale, Jason W., primary, Asara, John M., primary, Choi, Augustine M.K., primary, Finkel, Toren, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

18. Supplementary Figure 7 from Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Author

Parkhitko, Andrey A., primary, Priolo, Carmen, primary, Coloff, Jonathan L., primary, Yun, Jihye, primary, Wu, Julia J., primary, Mizumura, Kenji, primary, Xu, Wenping, primary, Malinowska, Izabela A., primary, Yu, Jane, primary, Kwiatkowski, David J., primary, Locasale, Jason W., primary, Asara, John M., primary, Choi, Augustine M.K., primary, Finkel, Toren, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

21. Supplementary Figure 6 from Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Author

Parkhitko, Andrey A., primary, Priolo, Carmen, primary, Coloff, Jonathan L., primary, Yun, Jihye, primary, Wu, Julia J., primary, Mizumura, Kenji, primary, Xu, Wenping, primary, Malinowska, Izabela A., primary, Yu, Jane, primary, Kwiatkowski, David J., primary, Locasale, Jason W., primary, Asara, John M., primary, Choi, Augustine M.K., primary, Finkel, Toren, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

22. Supplementary Figure 1 from Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide

Author

Parkhitko, Andrey A., primary, Priolo, Carmen, primary, Coloff, Jonathan L., primary, Yun, Jihye, primary, Wu, Julia J., primary, Mizumura, Kenji, primary, Xu, Wenping, primary, Malinowska, Izabela A., primary, Yu, Jane, primary, Kwiatkowski, David J., primary, Locasale, Jason W., primary, Asara, John M., primary, Choi, Augustine M.K., primary, Finkel, Toren, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

23. Supplementary Table S1 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Lam, Hilaire C., primary, Baglini, Christian V., primary, Lope, Alicia Llorente, primary, Parkhitko, Andrey A., primary, Liu, Heng-Jia, primary, Alesi, Nicola, primary, Malinowska, Izabela A., primary, Ebrahimi-Fakhari, Darius, primary, Saffari, Afshin, primary, Yu, Jane J., primary, Pereira, Ana, primary, Khabibullin, Damir, primary, Ogorek, Barbara, primary, Nijmeh, Julie, primary, Kavanagh, Taylor, primary, Handen, Adam, primary, Chan, Stephen Y., primary, Asara, John M., primary, Oldham, William M., primary, Diaz-Meco, Maria T., primary, Moscat, Jorge, primary, Sahin, Mustafa, primary, Priolo, Carmen, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

24. Raw data for Supplementary Table 1 and 2 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Lam, Hilaire C., primary, Baglini, Christian V., primary, Lope, Alicia Llorente, primary, Parkhitko, Andrey A., primary, Liu, Heng-Jia, primary, Alesi, Nicola, primary, Malinowska, Izabela A., primary, Ebrahimi-Fakhari, Darius, primary, Saffari, Afshin, primary, Yu, Jane J., primary, Pereira, Ana, primary, Khabibullin, Damir, primary, Ogorek, Barbara, primary, Nijmeh, Julie, primary, Kavanagh, Taylor, primary, Handen, Adam, primary, Chan, Stephen Y., primary, Asara, John M., primary, Oldham, William M., primary, Diaz-Meco, Maria T., primary, Moscat, Jorge, primary, Sahin, Mustafa, primary, Priolo, Carmen, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

25. Figure S4 from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Lam, Hilaire C., primary, Baglini, Christian V., primary, Lope, Alicia Llorente, primary, Parkhitko, Andrey A., primary, Liu, Heng-Jia, primary, Alesi, Nicola, primary, Malinowska, Izabela A., primary, Ebrahimi-Fakhari, Darius, primary, Saffari, Afshin, primary, Yu, Jane J., primary, Pereira, Ana, primary, Khabibullin, Damir, primary, Ogorek, Barbara, primary, Nijmeh, Julie, primary, Kavanagh, Taylor, primary, Handen, Adam, primary, Chan, Stephen Y., primary, Asara, John M., primary, Oldham, William M., primary, Diaz-Meco, Maria T., primary, Moscat, Jorge, primary, Sahin, Mustafa, primary, Priolo, Carmen, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

26. Supplementary Materials and Methods from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Lam, Hilaire C., primary, Baglini, Christian V., primary, Lope, Alicia Llorente, primary, Parkhitko, Andrey A., primary, Liu, Heng-Jia, primary, Alesi, Nicola, primary, Malinowska, Izabela A., primary, Ebrahimi-Fakhari, Darius, primary, Saffari, Afshin, primary, Yu, Jane J., primary, Pereira, Ana, primary, Khabibullin, Damir, primary, Ogorek, Barbara, primary, Nijmeh, Julie, primary, Kavanagh, Taylor, primary, Handen, Adam, primary, Chan, Stephen Y., primary, Asara, John M., primary, Oldham, William M., primary, Diaz-Meco, Maria T., primary, Moscat, Jorge, primary, Sahin, Mustafa, primary, Priolo, Carmen, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

27. Data from p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Lam, Hilaire C., primary, Baglini, Christian V., primary, Lope, Alicia Llorente, primary, Parkhitko, Andrey A., primary, Liu, Heng-Jia, primary, Alesi, Nicola, primary, Malinowska, Izabela A., primary, Ebrahimi-Fakhari, Darius, primary, Saffari, Afshin, primary, Yu, Jane J., primary, Pereira, Ana, primary, Khabibullin, Damir, primary, Ogorek, Barbara, primary, Nijmeh, Julie, primary, Kavanagh, Taylor, primary, Handen, Adam, primary, Chan, Stephen Y., primary, Asara, John M., primary, Oldham, William M., primary, Diaz-Meco, Maria T., primary, Moscat, Jorge, primary, Sahin, Mustafa, primary, Priolo, Carmen, primary, and Henske, Elizabeth P., primary

Published
2023
Full Text
View/download PDF

32. Trans-omics analysis of insulin action reveals a cell growth subnetwork which co-regulates anabolic processes

Author

Terakawa, Akira, primary, Hu, Yanhui, additional, Kokaji, Toshiya, additional, Yugi, Katsuyuki, additional, Morita, Keigo, additional, Ohno, Satoshi, additional, Pan, Yifei, additional, Bai, Yunfan, additional, Parkhitko, Andrey A., additional, Ni, Xiaochun, additional, Asara, John M., additional, Bulyk, Martha L., additional, Perrimon, Norbert, additional, and Kuroda, Shinya, additional

Published
2022
Full Text
View/download PDF

34. Trans-omic Analysis of Insulin Action Reveals a Sub-Network Required for Cell Growth Through Co-Regulated Gene Expression of Anabolic Processes

Author

Terakawa, Akira, primary, Hu, Yanhui, additional, Kokaji, Toshiya, additional, Yugi, Katsuyuki, additional, Morita, Keigo, additional, Ohno, Satoshi, additional, Pan, Yifei, additional, Bai, Yunfan, additional, Parkhitko, Andrey A., additional, Ni, Xiaochun, additional, Asara, John M., additional, Bulyk, Martha L., additional, Perrimon, Norbert, additional, and Kuroda, Shinya, additional

Published
2022
Full Text
View/download PDF

35. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4

Author

Csibi, Alfred, primary, Fendt, Sarah-Maria, additional, Li, Chenggang, additional, Poulogiannis, George, additional, Choo, Andrew Y., additional, Chapski, Douglas J., additional, Jeong, Seung Min, additional, Dempsey, Jamie M., additional, Parkhitko, Andrey, additional, Morrison, Tasha, additional, Henske, Elizabeth P., additional, Haigis, Marcia C., additional, Cantley, Lewis C., additional, Stephanopoulos, Gregory, additional, Yu, Jane, additional, and Blenis, John, additional

Published
2021
Full Text
View/download PDF

38. Downregulation of the tyrosine degradation pathway extends Drosophila lifespan

Author

Parkhitko, Andrey A, primary, Ramesh, Divya, additional, Wang, Lin, additional, Leshchiner, Dmitry, additional, Filine, Elizabeth, additional, Binari, Richard, additional, Olsen, Abby L, additional, Asara, John M, additional, Cracan, Valentin, additional, Rabinowitz, Joshua D, additional, Brockmann, Axel, additional, and Perrimon, Norbert, additional

Published
2020
Full Text
View/download PDF

39. Correction: p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Lam, Hilaire C., primary, Baglini, Christian V., additional, Lope, Alicia Llorente, additional, Parkhitko, Andrey A., additional, Liu, Heng-Jia, additional, Alesi, Nicola, additional, Malinowska, Izabela A., additional, Ebrahimi-Fakhari, Darius, additional, Saffari, Afshin, additional, Yu, Jane J., additional, Pereira, Ana, additional, Khabibullin, Damir, additional, Ogorek, Barbara, additional, Nijmeh, Julie, additional, Kavanagh, Taylor, additional, Handen, Adam, additional, Chan, Stephen Y., additional, Asara, John M., additional, Oldham, William M., additional, Diaz-Meco, Maria T., additional, Moscat, Jorge, additional, Sahin, Mustafa, additional, Priolo, Carmen, additional, and Henske, Elizabeth P., additional

Published
2020
Full Text
View/download PDF

40. Author response: Downregulation of the tyrosine degradation pathway extends Drosophila lifespan

Author

Parkhitko, Andrey A, primary, Ramesh, Divya, additional, Wang, Lin, additional, Leshchiner, Dmitry, additional, Filine, Elizabeth, additional, Binari, Richard, additional, Olsen, Abby L, additional, Asara, John M, additional, Cracan, Valentin, additional, Rabinowitz, Joshua D, additional, Brockmann, Axel, additional, and Perrimon, Norbert, additional

Published
2020
Full Text
View/download PDF

42. Lysosomal cystine efflux opposes mTORC1 reactivation through the TCA cycle

Author

Jouandin, Patrick, Marelja, Zvonimir, Parkhitko, Andrey A, Dambowsky, Miriam, Asara, John M, Nemazanyy, Ivan, Simons, Matias, and Perrimon, Norbert

Subjects
biological phenomena, cell phenomena, and immunity
Abstract

The highly regulated process of adapting to cellular nutritional status depends on lysosomal mTORC1 (mechanistic Target of Rapamycin Complex 1), that integrates nutrients availability via the sensing of amino acids to promote growth and anabolism 1 . Nutrient restriction inhibits mTORC1 activity, which in turn induces autophagy, a crucial adaptive process that recycles internal nutrient stores to promote survival 2 . However, as successful amino acid recycling through autophagic degradation reactivates mTORC1 signaling over time 3,4 , it is unclear how autophagy can be maintained during prolonged starvation. Here, we show that one particular amino acid, cysteine, acts in a feedback loop to limit mTORC1 reactivation in vivo . We provide evidence that lysosomal export of cystine through the cystine transporter cystinosin fuels a metabolic pathway that suppresses mTORC1 signaling and maintains autophagy during starvation. This pathway involves reduction to cysteine, cysteine catabolism to acetyl-CoA and subsequent fueling of the TCA cycle. Accordingly, the starvation sensitivity phenotype of animals lacking cystinosin is rescued by dietary supplementation with cysteine and TCA cycle components as well as by reducing mTORC1 activity. We propose that cysteine mediates a communication between lysosomes and mitochondria to control mTORC1 signaling under prolonged starvation, highlighting how changes in nutrient availability divert the fate of an amino acid into a growth suppressive program to maintain the balance between nutrient supply and consumption.

Published
2019
Full Text
View/download PDF

46. p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

Author

Lam, Hilaire C., primary, Baglini, Christian V., additional, Lope, Alicia Llorente, additional, Parkhitko, Andrey A., additional, Liu, Heng-Jia, additional, Alesi, Nicola, additional, Malinowska, Izabela A., additional, Ebrahimi-Fakhari, Darius, additional, Saffari, Afshin, additional, Yu, Jane J., additional, Pereira, Ana, additional, Khabibullin, Damir, additional, Ogorek, Barbara, additional, Nijmeh, Julie, additional, Kavanagh, Taylor, additional, Handen, Adam, additional, Chan, Stephen Y., additional, Asara, John M., additional, Oldham, William M., additional, Diaz-Meco, Maria T., additional, Moscat, Jorge, additional, Sahin, Mustafa, additional, Priolo, Carmen, additional, and Henske, Elizabeth P., additional

Published
2017
Full Text
View/download PDF

47. Abstract A35: Regulation of the tumor microenvironment by oncogenic p62 in mTORC1-hyperactive diseases: Tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM)

Author

Lam, Hilaire C., primary, Parkhitko, Andrey, additional, Lope, Alicia Llorente, additional, Alesi, Nicola, additional, Khabibullin, Damir, additional, Filippakis, Harilaos, additional, Pereira, Ana, additional, Ogorek, Barbara, additional, Zhang, Erik, additional, Yu, Jane, additional, Priolo, Carmen, additional, and Henske, Elizabeth P., additional

Published
2016
Full Text
View/download PDF

50. The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4

Author

Massachusetts Institute of Technology. Department of Chemical Engineering, Fendt, Sarah-Maria, Stephanopoulos, Gregory, Csibi, Alfred, Li, Chenggang, Poulogiannis, George, Choo, Andrew Y., Chapski, Douglas J., Jeong, Seung Min, Dempsey, Jamie M., Parkhitko, Andrey, Morrison, Tasha, Henske, Elizabeth P., Haigis, Marcia C., Cantley, Lewis C., Yu, Jane, Blenis, John, Massachusetts Institute of Technology. Department of Chemical Engineering, Fendt, Sarah-Maria, Stephanopoulos, Gregory, Csibi, Alfred, Li, Chenggang, Poulogiannis, George, Choo, Andrew Y., Chapski, Douglas J., Jeong, Seung Min, Dempsey, Jamie M., Parkhitko, Andrey, Morrison, Tasha, Henske, Elizabeth P., Haigis, Marcia C., Cantley, Lewis C., Yu, Jane, and Blenis, John

Abstract

Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach., German Science Foundation (Fellow FE-1185)

Published
2014

Catalog

Books, media, physical & digital resources
See catalog results