External seminar Reuben Shaw

AMPK control of growth, metabolism, and mitochondrial homeostasis

Reuben J. Shaw, Ph.D.

Professor, Molecular and Cell Biology Laboratory

Director, Salk NCI-Designated Cancer Center

The Salk Institute for Biological Studies, La Jolla, CA, USA 92037

Eukaryotic cells evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK). Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to re-program cellular metabolism from anabolism to catabolism. This energy switch suppresses pro-growth pathways (mTORC1 and fatty acid synthesis) while inducing autophagy and lysosomal function. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, via stimulation of autophagy, mitochondrial fission, and mitochondrial biogenesis. Here will present new data from our lab identifying key new steps and players in the mechanisms of AMPK controls mitochondrial homeostasis. This work has direct links to aging, metabolic disease, neurodegenerative diseases, and common forms of cancer in which this pathway is altered.

Selected publications

Zhang, T., Xu, D., Trefts, E., Lv, M., Inuzuka, H., Song, G., Liu, M., Lu, J., Liu, J., Chu, C., Wang, M., Wang, H., Meng, H., Liu, H., Zhuang, Y., Xie, X., Dang, F., Guan, D., Men, Y., Jiang, S., Jiang, C., Dai, X., Liu, J., Wang, Z., Yan, P., Wang, J., Tu, Z., Babuta, M., Erickson, E., Hillis, A.L., Dibble, C.C., Asara, J.M., Szabo, G., Sicinski, P., Miao, J., Lee, Y.R., Pan, L., Shaw, R.J., Yuan, J., Wei, W. Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.(2023) Science. 380(6652):1372-1380. DOI: 10.1126/science.abn1725” src=”blob:https://pgnm.inmg.fr/1f1507f7-3f68-4f0c-971c-5a0a17547a51″ alt=”image003.png” width=”13.5″ border=”0″ class=”Apple-web-attachment” style=”width: 0.2812in; height: 0.2812in; opacity: 1;”>
Kuna, R.S., Kumar, A., Wessendorf-Rodriguez, K.A., Galvez, H., Green, C.R., McGregor, G.H., Cordes, T., Shaw, R.J., Svensson, R.U., Metallo, C.M. Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.(2023) Science Advances. 9(18):eadf0138. DOI: 10.1126/sciadv.adf0138” src=”blob:https://pgnm.inmg.fr/1f1507f7-3f68-4f0c-971c-5a0a17547a51″ alt=”image003.png” width=”13.5″ border=”0″ class=”Apple-web-attachment” style=”width: 0.2812in; height: 0.2812in;”>
Malik, N., Ferreira, B.I., Hollstein, P.E., Curtis, S.D., Trefts, E., Weiser Novak, S., Yu, J., Gilson, R., Hellberg, K., Fang, L., Sheridan, A., Hah, N., Shadel, G.S., Manor, U., Shaw, R.J. Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1.(2023) Science. 380(6642):eabj5559. DOI: 10.1126/science.abj5559” src=”blob:https://pgnm.inmg.fr/1f1507f7-3f68-4f0c-971c-5a0a17547a51″ alt=”image003.png” width=”13.5″ border=”0″ class=”Apple-web-attachment” style=”width: 0.2812in; height: 0.2812in;”>
Eichner, L.J., Curtis, S.D., Brun, S.N., McGuire, C.K., Gushterova, I., Baumgart, J.T., Trefts, E., Ross, D.S., Rymoff, T.J., Shaw, R.J. HDAC3 is critical in tumor development and therapeutic resistance in -mutant non-small cell lung cancer.(2023) Science Advances. 9(11):eadd3243. DOI: 10.1126/sciadv.add3243” src=”blob:https://pgnm.inmg.fr/1f1507f7-3f68-4f0c-971c-5a0a17547a51″ alt=”image003.png” width=”13.5″ border=”0″ class=”Apple-web-attachment” style=”width: 0.2812in; height: 0.2812in;”>
Hung, C.M., Lombardo, P.S., Malik, N., Brun, S.N., Hellberg, K., Van Nostrand, J.L., Garcia, D., Baumgart, J., Diffenderfer, K., Asara, J.M., Shaw, R.J. AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy.(2021) Science Advances. 7(15). DOI: 10.1126/sciadv.abg4544” src=”blob:https://pgnm.inmg.fr/1f1507f7-3f68-4f0c-971c-5a0a17547a51″ alt=”image003.png” width=”13.5″ border=”0″ class=”Apple-web-attachment” style=”width: 0.2812in; height: 0.2812in;”>