Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms

English version

Autoři: Diana Bahhir ^aff001; Cagri Yalgin ^aff002; Liina Ots ^aff001; Sampsa Järvinen ^aff003; Jack George ^aff003; Alba Naudí ^aff004; Tatjana Krama ^aff005; Indrikis Krams ^aff005; Mairi Tamm ^aff001; Ana Andjelković ^aff003; Eric Dufour ^aff003; Jose M. González de Cózar ^aff003; Mike Gerards ^aff003; Mikael Parhiala ^aff003; Reinald Pamplona ^aff004; Howard T. Jacobs ^aff003; Priit Jõers ^aff001
Působiště autorů: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia ^aff001; Institute of Biotechnology, University of Helsinki, Helsinki, Finland ^aff002; Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland ^aff003; Experimental Medicine Department, University of Lleida-Institute for Research in Biomedicine of Lleida (UdL-IRBLLEIDA), Lleida, Spain ^aff004; Institute of Ecology and Earth Sciences, University of Tartu, Tartu, Estonia ^aff005; Department of Plant Health, Institute of Agricultural and Environmental Sciences, Estonian University of Life Science, Tartu, Estonia ^aff006; Department of Zoology and Animal Ecology, Faculty of Biology, University of Latvia, Rīga, Latvia ^aff007; Department of Biotechnology, Daugavpils University, Daugavpils, Latvia ^aff008; Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands ^aff009
Vyšlo v časopise: Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008410
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008410

Souhrn

Mitochondria have been increasingly recognized as a central regulatory nexus for multiple metabolic pathways, in addition to ATP production via oxidative phosphorylation (OXPHOS). Here we show that inducing mitochondrial DNA (mtDNA) stress in Drosophila using a mitochondrially-targeted Type I restriction endonuclease (mtEcoBI) results in unexpected metabolic reprogramming in adult flies, distinct from effects on OXPHOS. Carbohydrate utilization was repressed, with catabolism shifted towards lipid oxidation, accompanied by elevated serine synthesis. Cleavage and translocation, the two modes of mtEcoBI action, repressed carbohydrate rmetabolism via two different mechanisms. DNA cleavage activity induced a type II diabetes-like phenotype involving deactivation of Akt kinase and inhibition of pyruvate dehydrogenase, whilst translocation decreased post-translational protein acetylation by cytonuclear depletion of acetyl-CoA (AcCoA). The associated decease in the concentrations of ketogenic amino acids also produced downstream effects on physiology and behavior, attributable to decreased neurotransmitter levels. We thus provide evidence for novel signaling pathways connecting mtDNA to metabolism, distinct from its role in supporting OXPHOS.

Klíčová slova:

Carbohydrates – Drosophila melanogaster – Larvae – Mitochondria – Mitochondrial DNA – Protein metabolism – Pyruvate – Acetylation

Zdroje

1. Suomalainen A, Battersby BJ. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat Rev Mol Cell Biol. 2018;19(2):77–92. doi: 10.1038/nrm.2017.66 28792006

2. Quiros PM, Mottis A, Auwerx J. Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol. 2016;17(4):213–26. doi: 10.1038/nrm.2016.23 26956194

3. Galluzzi L, Kepp O, Kroemer G. Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol. 2012;13(12):780–8. doi: 10.1038/nrm3479 23175281

4. Chandel NS. Mitochondria as signaling organelles. BMC Biol. 2014;12:34. doi: 10.1186/1741-7007-12-34 24884669

5. Kim KH, Lee MS. FGF21 as a stress hormone: the roles of FGF21 in stress adaptation and the treatment of metabolic diseases. Diabetes Metab J. 2014;38(4):245–51. doi: 10.4093/dmj.2014.38.4.245 25215270

6. Lehtonen JM, Forsstrom S, Bottani E, Viscomi C, Baris OR, Isoniemi H, et al. FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders. Neurology. 2016;87(22):2290–9. doi: 10.1212/WNL.0000000000003374 27794108

7. Frezza C. Mitochondrial metabolites: undercover signalling molecules. Interface Focus. 2017;7(2):20160100. doi: 10.1098/rsfs.2016.0100 28382199

8. Su X, Wellen KE, Rabinowitz JD. Metabolic control of methylation and acetylation. Curr Opin Chem Biol. 2016;30:52–60. doi: 10.1016/j.cbpa.2015.10.030 26629854

9. Martinez-Pastor B, Cosentino C, Mostoslavsky R. A tale of metabolites: the cross-talk between chromatin and energy metabolism. Cancer Discov. 2013;3(5):497–501. doi: 10.1158/2159-8290.CD-13-0059 23658298

10. Spelbrink JN. Functional organization of mammalian mitochondrial DNA in nucleoids: history, recent developments, and future challenges. IUBMB Life. 2010;62(1):19–32. doi: 10.1002/iub.282 20014006

11. Bogenhagen DF, Rousseau D, Burke S. The layered structure of human mitochondrial DNA nucleoids. J Biol Chem. 2008;283(6):3665–75. doi: 10.1074/jbc.M708444200 18063578

12. Litwin TR, Sola M, Holt IJ, Neuman KC. A robust assay to measure DNA topology-dependent protein binding affinity. Nucleic Acids Res. 2015;43(7):e43. doi: 10.1093/nar/gku1381 25552413

13. Kukat C, Davies KM, Wurm CA, Spahr H, Bonekamp NA, Kuhl I, et al. Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid. Proc Natl Acad Sci U S A. 2015;112(36):11288–93. doi: 10.1073/pnas.1512131112 26305956

14. Ngo HB, Kaiser JT, Chan DC. The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA. Nat Struct Mol Biol. 2011;18(11):1290–6. doi: 10.1038/nsmb.2159 22037171

15. Gilkerson R, Bravo L, Garcia I, Gaytan N, Herrera A, Maldonado A, et al. The mitochondrial nucleoid: integrating mitochondrial DNA into cellular homeostasis. Cold Spring Harb Perspect Biol. 2013;5(5):a011080. doi: 10.1101/cshperspect.a011080 23637282

16. West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015;520(7548):553–7. doi: 10.1038/nature14156 25642965

17. Shi Y, Dierckx A, Wanrooij PH, Wanrooij S, Larsson NG, Wilhelmsson LM, et al. Mammalian transcription factor A is a core component of the mitochondrial transcription machinery. Proc Natl Acad Sci U S A. 2012;109(41):16510–5. doi: 10.1073/pnas.1119738109 23012404

18. Tyynismaa H, Mjosund KP, Wanrooij S, Lappalainen I, Ylikallio E, Jalanko A, et al. Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice. Proc Natl Acad Sci U S A. 2005;102(49):17687–92. doi: 10.1073/pnas.0505551102 16301523

19. Tyynismaa H, Carroll CJ, Raimundo N, Ahola-Erkkila S, Wenz T, Ruhanen H, et al. Mitochondrial myopathy induces a starvation-like response. Hum Mol Genet. 2010;19(20):3948–58. doi: 10.1093/hmg/ddq310 20656789

20. Nikkanen J, Forsstrom S, Euro L, Paetau I, Kohnz RA, Wang L, et al. Mitochondrial DNA replication defects disturb cellular dNTP pools and remodel one-carbon metabolism. Cell Metab. 2016;23(4):635–48. doi: 10.1016/j.cmet.2016.01.019 26924217

21. Murray NE. Type I restriction systems: sophisticated molecular machines (a legacy of Bertani and Weigle). Microbiol Mol Biol Rev. 2000;64(2):412–34. doi: 10.1128/mmbr.64.2.412-434.2000 10839821

22. Bao XR, Ong SE, Goldberger O, Peng J, Sharma R, Thompson DA, et al. Mitochondrial dysfunction remodels one-carbon metabolism in human cells. Elife. 2016;5.

23. Quiros PM, Prado MA, Zamboni N, D'Amico D, Williams RW, Finley D, et al. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J Cell Biol. 2017;216(7):2027–45. doi: 10.1083/jcb.201702058 28566324

24. Xu H, DeLuca SZ, O'Farrell PH. Manipulating the metazoan mitochondrial genome with targeted restriction enzymes. Science. 2008;321(5888):575–7. doi: 10.1126/science.1160226 18653897

25. Davies GP, Kemp P, Molineux IJ, Murray NE. The DNA translocation and ATPase activities of restriction-deficient mutants of Eco KI. J Mol Biol. 1999;292(4):787–96. doi: 10.1006/jmbi.1999.3081 10525405

26. Rebelo AP, Williams SL, Moraes CT. In vivo methylation of mtDNA reveals the dynamics of protein-mtDNA interactions. Nucleic Acids Res. 2009;37(20):6701–15. doi: 10.1093/nar/gkp727 19740762

27. Hangas A, Aasumets K, Kekalainen NJ, Paloheina M, Pohjoismaki JL, Gerhold JM, et al. Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2. Nucleic Acids Res. 2018;46(18):9625–36. doi: 10.1093/nar/gky793 30169847

28. Owusu-Ansah E, Banerjee U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature. 2009;461(7263):537–41. doi: 10.1038/nature08313 19727075

29. Niccoli T, Cabecinha M, Tillmann A, Kerr F, Wong CT, Cardenes D, et al. Increased glucose transport into neurons rescues Aβ toxicity in Drosophila. Curr Biol. 2016;26(18):2550.

30. Owusu-Ansah E, Song W, Perrimon N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell. 2013;155(3):699–712. doi: 10.1016/j.cell.2013.09.021 24243023

31. Riemensperger T, Isabel G, Coulom H, Neuser K, Seugnet L, Kume K, et al. Behavioral consequences of dopamine deficiency in the Drosophila central nervous system. Proc Natl Acad Sci U S A. 2011;108(2):834–9. doi: 10.1073/pnas.1010930108 21187381

32. Yamamoto S, Seto ES. Dopamine dynamics and signaling in Drosophila: an overview of genes, drugs and behavioral paradigms. Exp Anim. 2014;63(2):107–19. doi: 10.1538/expanim.63.107 24770636

33. Monastirioti M, Linn CE Jr., White K. Characterization of Drosophila tyramine beta-hydroxylase gene and isolation of mutant flies lacking octopamine. J Neurosci. 1996;16(12):3900–11. 8656284

34. Monastirioti M. Distinct octopamine cell population residing in the CNS abdominal ganglion controls ovulation in Drosophila melanogaster. Dev Biol. 2003;264(1):38–49. doi: 10.1016/j.ydbio.2003.07.019 14623230

35. Janscak P, Bickle TA. DNA supercoiling during ATP-dependent DNA translocation by the type I restriction enzyme EcoAI. J Mol Biol. 2000;295(4):1089–99. doi: 10.1006/jmbi.1999.3414 10656812

36. Marino G, Pietrocola F, Eisenberg T, Kong Y, Malik SA, Andryushkova A, et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol Cell. 2014;53(5):710–25. doi: 10.1016/j.molcel.2014.01.016 24560926

37. Morciano P, Carrisi C, Capobianco L, Mannini L, Burgio G, Cestra G, et al. A conserved role for the mitochondrial citrate transporter Sea/SLC25A1 in the maintenance of chromosome integrity. Hum Mol Genet. 2009;18(21):4180–8. doi: 10.1093/hmg/ddp370 19654186

38. Rajamohan SB, Pillai VB, Gupta M, Sundaresan NR, Birukov KG, Samant S, et al. SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1. Mol Cell Biol. 2009;29(15):4116–29. doi: 10.1128/MCB.00121-09 19470756

39. Srivastava S, Moraes CT. Double-strand breaks of mouse muscle mtDNA promote large deletions similar to multiple mtDNA deletions in humans. Hum Mol Genet. 2005;14(7):893–902. doi: 10.1093/hmg/ddi082 15703189

40. Nissanka N, Moraes CT. Mitochondrial DNA damage and reactive oxygen species in neurodegenerative disease. FEBS Lett. 2018;592(5):728–42. doi: 10.1002/1873-3468.12956 29281123

41. Peeva V, Blei D, Trombly G, Corsi S, Szukszto MJ, Rebelo-Guiomar P, et al. Linear mitochondrial DNA is rapidly degraded by components of the replication machinery. Nat Commun. 2018;9(1):1727. doi: 10.1038/s41467-018-04131-w 29712893

42. Kauppila TES, Bratic A, Jensen MB, Baggio F, Partridge L, Jasper H, et al. Mutations of mitochondrial DNA are not major contributors to aging of fruit flies. Proc Natl Acad Sci U S A. 2018;115(41):E9620–E9. doi: 10.1073/pnas.1721683115 30249665

43. Hensen F, Cansiz S, Gerhold JM, Spelbrink JN. To be or not to be a nucleoid protein: a comparison of mass-spectrometry based approaches in the identification of potential mtDNA-nucleoid associated proteins. Biochimie. 2014;100:219–26. doi: 10.1016/j.biochi.2013.09.017 24076128

44. Bogenhagen DF. Mitochondrial DNA nucleoid structure. Biochim Biophys Acta. 2012;1819(9–10):914–20. doi: 10.1016/j.bbagrm.2011.11.005 22142616

45. Rajala N, Hensen F, Wessels HJ, Ives D, Gloerich J, Spelbrink JN. Whole cell formaldehyde cross-linking simplifies purification of mitochondrial nucleoids and associated proteins involved in mitochondrial gene expression. PLoS One. 2015;10(2):e0116726. doi: 10.1371/journal.pone.0116726 25695250

46. Kucej M, Kucejova B, Subramanian R, Chen XJ, Butow RA. Mitochondrial nucleoids undergo remodeling in response to metabolic cues. J Cell Sci. 2008;121(11):1861–8. doi: 10.1242/jcs.028605 18477605

47. Chen XJ, Wang X, Kaufman BA, Butow RA. Aconitase couples metabolic regulation to mitochondrial DNA maintenance. Science. 2005;307(5710):714–7. doi: 10.1126/science.1106391 15692048

48. Martinez-Reyes I, Diebold LP, Kong H, Schieber M, Huang H, Hensley CT, et al. TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol Cell. 2016;61(2):199–209. doi: 10.1016/j.molcel.2015.12.002 26725009

49. Lozoya OA, Martinez-Reyes I, Wang T, Grenet D, Bushel P, Li J, et al. Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation. PLoS Biol. 2018;16(4):e2005707. doi: 10.1371/journal.pbio.2005707 29668680

50. Hakimi P, Yang J, Casadesus G, Massillon D, Tolentino-Silva F, Nye CK, et al. Overexpression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse. J Biol Chem. 2007;282(45):32844–55. doi: 10.1074/jbc.M706127200 17716967

51. Han SK, Lee D, Lee H, Kim D, Son HG, Yang JS, et al. OASIS 2: online application for survival analysis 2 with features for the analysis of maximal lifespan and healthspan in aging research. Oncotarget. 2016;7(35):56147–52. doi: 10.18632/oncotarget.11269 27528229

52. Rorth P. Gal4 in the Drosophila female germline. Mech Dev. 1998;78(1–2):113–8. doi: 10.1016/s0925-4773(98)00157-9 9858703

53. Barolo S, Carver LA, Posakony JW. GFP and beta-galactosidase transformation vectors for promoter/enhancer analysis in Drosophila. Biotechniques. 2000;29(4):726, 8, 30, 32. doi: 10.2144/00294bm10 11056799

54. Kunkel TA, Roberts JD, Zakour RA. Rapid and efficient site-specific mutagenesis without phenotypic selection. Methods Enzymol. 1987;154:367–82. doi: 10.1016/0076-6879(87)54085-x 3323813

55. Bischof J, Maeda RK, Hediger M, Karch F, Basler K. An optimized transgenesis system for Drosophila using germ-line-specific phiC31 integrases. Proc Natl Acad Sci U S A. 2007;104(9):3312–7. doi: 10.1073/pnas.0611511104 17360644

56. Radyuk SN, Rebrin I, Klichko VI, Sohal BH, Michalak K, Benes J, et al. Mitochondrial peroxiredoxins are critical for the maintenance of redox state and the survival of adult Drosophila. Free Radic Biol Med. 2010;49(12):1892–902. doi: 10.1016/j.freeradbiomed.2010.09.014 20869434

57. Albrecht SC, Barata AG, Grosshans J, Teleman AA, Dick TP. In vivo mapping of hydrogen peroxide and oxidized glutathione reveals chemical and regional specificity of redox homeostasis. Cell Metab. 2011;14(6):819–29. doi: 10.1016/j.cmet.2011.10.010 22100409

58. Tokusumi T, Shoue DA, Tokusumi Y, Stoller JR, Schulz RA. New hemocyte-specific enhancer-reporter transgenes for the analysis of hematopoiesis in Drosophila. Genesis. 2009;47(11):771–4. doi: 10.1002/dvg.20561 19830816

59. Fernandez-Ayala DJ, Sanz A, Vartiainen S, Kemppainen KK, Babusiak M, Mustalahti E, et al. Expression of the Ciona intestinalis alternative oxidase (AOX) in Drosophila complements defects in mitochondrial oxidative phosphorylation. Cell Metab. 2009;9(5):449–60. doi: 10.1016/j.cmet.2009.03.004 19416715

60. Joers P, Jacobs HT. Analysis of replication intermediates indicates that Drosophila melanogaster mitochondrial DNA replicates by a strand-coupled theta mechanism. PLoS One. 2013;8(1):e53249. doi: 10.1371/journal.pone.0053249 23308172

61. Rogers SL, Rogers GC. Culture of Drosophila S2 cells and their use for RNAi-mediated loss-of-function studies and immunofluorescence microscopy. Nat Protoc. 2008;3(4):606–11. doi: 10.1038/nprot.2008.18 18388942

62. Barrio L, Dekanty A, Milan M. MicroRNA-mediated regulation of Dp53 in the Drosophila fat body contributes to metabolic adaptation to nutrient deprivation. Cell Rep. 2014;8(2):528–41. doi: 10.1016/j.celrep.2014.06.020 25017064