Induction of Lysosomal and Mitochondrial Biogenesis by AMPK Phosphorylation of FNIP1

Overview

Journal Science

Specialty Science

Date 2023 Apr 20

PMID 37079666

Authors

Nazma Malik

Bibiana I Ferreira

Pablo E Hollstein

Stephanie D Curtis

Elijah Trefts

Sammy Weiser Novak

Jingting Yu

Rebecca Gilson

Kristina Hellberg

Lingjing Fang

Arlo Sheridan

Nasun Hah

Gerald S Shadel

Uri Manor

Reuben J Shaw

Affiliations

Soon will be listed here.

Abstract

Cells respond to mitochondrial poisons with rapid activation of the adenosine monophosphate-activated protein kinase (AMPK), causing acute metabolic changes through phosphorylation and prolonged adaptation of metabolism through transcriptional effects. Transcription factor EB (TFEB) is a major effector of AMPK that increases expression of lysosome genes in response to energetic stress, but how AMPK activates TFEB remains unresolved. We demonstrate that AMPK directly phosphorylates five conserved serine residues in folliculin-interacting protein 1 (FNIP1), suppressing the function of the folliculin (FLCN)-FNIP1 complex. FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB and TFEB-dependent increases of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and estrogen-related receptor alpha (ERRα) messenger RNAs. Thus, mitochondrial damage triggers AMPK-FNIP1-dependent nuclear translocation of TFEB, inducing sequential waves of lysosomal and mitochondrial biogenesis.

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References

Steinberg G, Carling D . AMP-activated protein kinase: the current landscape for drug development. Nat Rev Drug Discov. 2019; 18(7):527-551. DOI: 10.1038/s41573-019-0019-2. View

Reyes N, Banks G, Tsang M, Margineantu D, Gu H, Djukovic D . Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy. Proc Natl Acad Sci U S A. 2014; 112(2):424-9. PMC: 4299192. DOI: 10.1073/pnas.1413021112. View

Palmieri M, Impey S, Kang H, di Ronza A, Pelz C, Sardiello M . Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum Mol Genet. 2011; 20(19):3852-66. DOI: 10.1093/hmg/ddr306. View

Babicki S, Arndt D, Marcu A, Liang Y, Grant J, Maciejewski A . Heatmapper: web-enabled heat mapping for all. Nucleic Acids Res. 2016; 44(W1):W147-53. PMC: 4987948. DOI: 10.1093/nar/gkw419. View

Heinz S, Benner C, Spann N, Bertolino E, Lin Y, Laslo P . Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010; 38(4):576-89. PMC: 2898526. DOI: 10.1016/j.molcel.2010.05.004. View

Gonzalez A, Hall M, Lin S, Grahame Hardie D . AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control. Cell Metab. 2020; 31(3):472-492. DOI: 10.1016/j.cmet.2020.01.015. View

Bergeron R, Ren J, Cadman K, Moore I, Perret P, Pypaert M . Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab. 2001; 281(6):E1340-6. DOI: 10.1152/ajpendo.2001.281.6.E1340. View

Hung C, Lombardo P, Malik N, Brun S, Hellberg K, Van Nostrand J . AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy. Sci Adv. 2021; 7(15). PMC: 8026119. DOI: 10.1126/sciadv.abg4544. View

Baba M, Hong S, Sharma N, Warren M, Nickerson M, Iwamatsu A . Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A. 2006; 103(42):15552-7. PMC: 1592464. DOI: 10.1073/pnas.0603781103. View

10.

Paquette M, El-Houjeiri L, Zirden L, Puustinen P, Blanchette P, Jeong H . AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3. Autophagy. 2021; 17(12):3957-3975. PMC: 8726606. DOI: 10.1080/15548627.2021.1898748. View

11.

Sardiello M, Palmieri M, di Ronza A, Medina D, Valenza M, Gennarino V . A gene network regulating lysosomal biogenesis and function. Science. 2009; 325(5939):473-7. DOI: 10.1126/science.1174447. View

12.

Huss J, Torra I, Staels B, Giguere V, Kelly D . Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol Cell Biol. 2004; 24(20):9079-91. PMC: 517878. DOI: 10.1128/MCB.24.20.9079-9091.2004. View

13.

Roczniak-Ferguson A, Petit C, Froehlich F, Qian S, Ky J, Angarola B . The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal. 2012; 5(228):ra42. PMC: 3437338. DOI: 10.1126/scisignal.2002790. View

14.

Goedhart J, Luijsterburg M . VolcaNoseR is a web app for creating, exploring, labeling and sharing volcano plots. Sci Rep. 2020; 10(1):20560. PMC: 7689420. DOI: 10.1038/s41598-020-76603-3. View

15.

Myers R, Guan H, Ehrhart J, Petrov A, Prahalada S, Tozzo E . Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy. Science. 2017; 357(6350):507-511. DOI: 10.1126/science.aah5582. View

16.

Collodet C, Foretz M, Deak M, Bultot L, Metairon S, Viollet B . AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR. FASEB J. 2019; 33(11):12374-12391. PMC: 6902666. DOI: 10.1096/fj.201900841R. View

17.

Chang J, Ghosh S, Newman S, Salbaum J . A map of the PGC-1α- and NT-PGC-1α-regulated transcriptional network in brown adipose tissue. Sci Rep. 2018; 8(1):7876. PMC: 5959870. DOI: 10.1038/s41598-018-26244-4. View

18.

Napolitano G, Di Malta C, Esposito A, de Araujo M, Pece S, Bertalot G . A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome. Nature. 2020; 585(7826):597-602. PMC: 7610377. DOI: 10.1038/s41586-020-2444-0. View

19.

Olson B, Hock M, Ekholm-Reed S, Wohlschlegel J, Dev K, Kralli A . SCFCdc4 acts antagonistically to the PGC-1alpha transcriptional coactivator by targeting it for ubiquitin-mediated proteolysis. Genes Dev. 2008; 22(2):252-64. PMC: 2192758. DOI: 10.1101/gad.1624208. View

20.

Gwinn D, Shackelford D, Egan D, Mihaylova M, Mery A, Vasquez D . AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008; 30(2):214-26. PMC: 2674027. DOI: 10.1016/j.molcel.2008.03.003. View