AMPK Activation Promotes Lipid Droplet Dispersion on Detyrosinated Microtubules to Increase Mitochondrial Fatty Acid Oxidation

Overview

Journal Nat Commun

Specialty Biology

Date 2015 May 28

PMID 26013497

Citations 136

Authors

Albert Herms

Marta Bosch

Babu J N Reddy

Nicole L Schieber

Alba Fajardo

Celia Ruperez

Andrea Fernandez-Vidal

Charles Ferguson

Carles Rentero

Francesc Tebar

Carlos Enrich

Robert G Parton

Steven P Gross

Albert Pol

Affiliations

Soon will be listed here.

Abstract

Lipid droplets (LDs) are intracellular organelles that provide fatty acids (FAs) to cellular processes including synthesis of membranes and production of metabolic energy. While known to move bidirectionally along microtubules (MTs), the role of LD motion and whether it facilitates interaction with other organelles are unclear. Here we show that during nutrient starvation, LDs and mitochondria relocate on detyrosinated MT from the cell centre to adopt a dispersed distribution. In the cell periphery, LD-mitochondria interactions increase and LDs efficiently supply FAs for mitochondrial beta-oxidation. This cellular adaptation requires the activation of the energy sensor AMPK, which in response to starvation simultaneously increases LD motion, reorganizes the network of detyrosinated MTs and activates mitochondria. In conclusion, we describe the existence of a specialized cellular network connecting the cellular energetic status and MT dynamics to coordinate the functioning of LDs and mitochondria during nutrient scarcity.

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References

Aon M, Bhatt N, Cortassa S . Mitochondrial and cellular mechanisms for managing lipid excess. Front Physiol. 2014; 5:282. PMC: 4116787. DOI: 10.3389/fphys.2014.00282. View

Jones R, Plas D, Kubek S, Buzzai M, Mu J, Xu Y . AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 2005; 18(3):283-93. DOI: 10.1016/j.molcel.2005.03.027. View

Cabodevilla A, Sanchez-Caballero L, Nintou E, Boiadjieva V, Picatoste F, Gubern A . Cell survival during complete nutrient deprivation depends on lipid droplet-fueled β-oxidation of fatty acids. J Biol Chem. 2013; 288(39):27777-88. PMC: 3784694. DOI: 10.1074/jbc.M113.466656. View

Kaul N, Soppina V, Verhey K . Effects of α-tubulin K40 acetylation and detyrosination on kinesin-1 motility in a purified system. Biophys J. 2014; 106(12):2636-43. PMC: 4070028. DOI: 10.1016/j.bpj.2014.05.008. View

Herms A, Bosch M, Ariotti N, Reddy B, Fajardo A, Fernandez-Vidal A . Cell-to-cell heterogeneity in lipid droplets suggests a mechanism to reduce lipotoxicity. Curr Biol. 2013; 23(15):1489-96. PMC: 3746173. DOI: 10.1016/j.cub.2013.06.032. View

Barlan K, Gelfand V . Intracellular transport: ER and mitochondria meet and greet along designated tracks. Curr Biol. 2010; 20(19):R845-7. DOI: 10.1016/j.cub.2010.08.058. View

Reid B, Ables G, Otlivanchik O, Schoiswohl G, Zechner R, Blaner W . Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis. J Biol Chem. 2008; 283(19):13087-99. PMC: 2442319. DOI: 10.1074/jbc.M800533200. View

Koves T, Ussher J, Noland R, Slentz D, Mosedale M, Ilkayeva O . Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008; 7(1):45-56. DOI: 10.1016/j.cmet.2007.10.013. View

Tong L, Harwood Jr H . Acetyl-coenzyme A carboxylases: versatile targets for drug discovery. J Cell Biochem. 2006; 99(6):1476-88. PMC: 3837461. DOI: 10.1002/jcb.21077. View

10.

Geeraert C, Ratier A, Pfisterer S, Perdiz D, Cantaloube I, Rouault A . Starvation-induced hyperacetylation of tubulin is required for the stimulation of autophagy by nutrient deprivation. J Biol Chem. 2010; 285(31):24184-94. PMC: 2911293. DOI: 10.1074/jbc.M109.091553. View

11.

Wloga D, Gaertig J . Post-translational modifications of microtubules. J Cell Sci. 2010; 123(Pt 20):3447-55. PMC: 2951466. DOI: 10.1242/jcs.063727. View

12.

Daval M, Foufelle F, Ferre P . Functions of AMP-activated protein kinase in adipose tissue. J Physiol. 2006; 574(Pt 1):55-62. PMC: 1817807. DOI: 10.1113/jphysiol.2006.111484. View

13.

Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M . Autophagy regulates lipid metabolism. Nature. 2009; 458(7242):1131-5. PMC: 2676208. DOI: 10.1038/nature07976. View

14.

Welte M, Cermelli S, Griner J, Viera A, Guo Y, Kim D . Regulation of lipid-droplet transport by the perilipin homolog LSD2. Curr Biol. 2005; 15(14):1266-75. DOI: 10.1016/j.cub.2005.06.062. View

15.

Pol A, Luetterforst R, Lindsay M, Heino S, Ikonen E, Parton R . A caveolin dominant negative mutant associates with lipid bodies and induces intracellular cholesterol imbalance. J Cell Biol. 2001; 152(5):1057-70. PMC: 2198820. DOI: 10.1083/jcb.152.5.1057. View

16.

Welte M . Fat on the move: intracellular motion of lipid droplets. Biochem Soc Trans. 2009; 37(Pt 5):991-6. DOI: 10.1042/BST0370991. View

17.

Gomes L, Benedetto G, Scorrano L . During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol. 2011; 13(5):589-98. PMC: 3088644. DOI: 10.1038/ncb2220. View

18.

Friedman J, Webster B, Mastronarde D, Verhey K, Voeltz G . ER sliding dynamics and ER-mitochondrial contacts occur on acetylated microtubules. J Cell Biol. 2010; 190(3):363-75. PMC: 2922647. DOI: 10.1083/jcb.200911024. View

19.

Marcinkiewicz A, Gauthier D, Garcia A, Brasaemle D . The phosphorylation of serine 492 of perilipin a directs lipid droplet fragmentation and dispersion. J Biol Chem. 2006; 281(17):11901-9. DOI: 10.1074/jbc.M600171200. View

20.

Shubeita G, Tran S, Xu J, Vershinin M, Cermelli S, Cotton S . Consequences of motor copy number on the intracellular transport of kinesin-1-driven lipid droplets. Cell. 2008; 135(6):1098-107. PMC: 2768369. DOI: 10.1016/j.cell.2008.10.021. View