Advertisement

Introduction: Mitochondria, the Cell Furnaces

  • Paulo J. Oliveira
Chapter

Abstract

In the motion picture “The Phantom Menace”, the Star Wars episode that caused so much controversy for fans of the series, Qui-Gon Jinn describes the source of the Jedi Force to Anakin Skywalker. “Without the midi-chlorians, life could not exist, and we would have no knowledge of the Force. They continually speak to us, telling us the will of the Force. When you learn to quiet your mind, you’ll hear them speaking to you…”. The Star Wars lore suggests that midi-chlorians are intelligent microscopic life forms that live symbiotically inside the cells of all living things, with higher numbers present in individuals with the ability to feel the Force. Does this sound familiar? Yes, it is a crude description of mitochondria, the former symbiotic bacteria that are now the cell powerhouses, among other critical roles in cell metabolism, calcium and redox signaling, and regulation of cell death processes. With multiple shapes and forms, mitochondria are an amazingly complex organelle, which never ceases to surprise the researchers with new and important functions in the context of cell metabolism. Moreover, the idea that mitochondria are an attractive drug target has been gaining traction in the last years, with two molecules claimed to target mitochondria already in the market.

Keywords

Mitochondria Furnace Disease Therapy Metabolism 

Notes

Acknowledgements

We are extremely thankfully to Alexandra Holy, MBA/MPP, Mills College, Oakland, CA, USA for proofreading English language in this text.Work in the author’s laboratory is funded by FEDER funds through the Operational Programme Competitiveness Factors—COMPETE and national funds by FCT—Foundation for Science and Technology under research grants PTDC/DTP-FTO/2433/2014, POCI-01-0145-FEDER-016659, and POCI-01-0145-FEDER-007440.

References

  1. Atienzar FA, Blomme EA, Chen M, Hewitt P, Kenna JG, Labbe G, Moulin F, Pognan F, Roth AB, Suter-Dick L, Ukairo O, Weaver RJ, Will Y, Dambach DM (2016) Key challenges and opportunities associated with the use of in vitro models to detect human DILI: integrated risk assessment and mitigation plans. Biomed Res Int 2016:9737920.  https://doi.org/10.1155/2016/9737920 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bacalhau M, Pratas J, Simoes M, Mendes C, Ribeiro C, Santos MJ, Diogo L, Macario MC, Grazina M (2017) In silico analysis for predicting pathogenicity of five unclassified mitochondrial DNA mutations associated with mitochondrial cytopathies' phenotypes. Eur J Med Genet 60(3):172–177.  https://doi.org/10.1016/j.ejmg.2016.12.009 CrossRefPubMedGoogle Scholar
  3. Barbosa IA, Machado NG, Skildum AJ, Scott PM, Oliveira PJ (2012) Mitochondrial remodeling in cancer metabolism and survival: potential for new therapies. Biochim Biophys Acta 1826(1):238–254.  https://doi.org/10.1016/j.bbcan.2012.04.005 PubMedGoogle Scholar
  4. Barua S, Junaid MA (2015) Lifestyle, pregnancy and epigenetic effects. Epigenomics 7(1):85–102.  https://doi.org/10.2217/epi.14.71 CrossRefPubMedGoogle Scholar
  5. Carvalho C, Santos RX, Cardoso S, Correia S, Oliveira PJ, Santos MS, Moreira PI (2009) Doxorubicin: the good, the bad and the ugly effect. Curr Med Chem 16(25):3267–3285CrossRefPubMedGoogle Scholar
  6. Carvalho FS, Burgeiro A, Garcia R, Moreno AJ, Carvalho RA, Oliveira PJ (2014) Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med Res Rev 34(1):106–135.  https://doi.org/10.1002/med.21280 CrossRefPubMedGoogle Scholar
  7. de Castro Fonseca M, Aguiar CJ, da Rocha Franco JA, Gingold RN, Leite MF (2016) GPR91: expanding the frontiers of Krebs cycle intermediates. Cell Commun Signal 14:3.  https://doi.org/10.1186/s12964-016-0126-1 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chretien D, Benit P, Ha H-H, Keipert S, El-Khoury R, Chang Y-T, Jastroch M, Jacobs H, Rustin P, Malgorzata R (2017) Mitochondria are physiologically maintained at close to 50 C. bioRxiv.  https://doi.org/10.1101/133223
  9. Craven L, Alston CL, Taylor RW, Turnbull DM (2017) Recent advances in mitochondrial disease. Annu Rev Genomics Hum Genet 18:257–275.  https://doi.org/10.1146/annurev-genom-091416-035426 CrossRefPubMedGoogle Scholar
  10. Degli Esposti M (2014) Bioenergetic evolution in proteobacteria and mitochondria. Genome Biol Evol 6(12):3238–3251.  https://doi.org/10.1093/gbe/evu257 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Devarshi PP, McNabney SM, Henagan TM (2017) Skeletal muscle nucleo-mitochondrial crosstalk in obesity and Type 2 diabetes. Int J Mol Sci 18(4):E831.  https://doi.org/10.3390/ijms18040831 CrossRefPubMedGoogle Scholar
  12. Duann P, Lin PH (2017) Mitochondria damage and kidney disease. Adv Exp Med Biol 982:529–551.  https://doi.org/10.1007/978-3-319-55330-6_27 CrossRefPubMedGoogle Scholar
  13. Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, Choi AM, Chu CT, Codogno P, Colombo MI, Cuervo AM, Debnath J, Deretic V, Dikic I, Eskelinen EL, Fimia GM, Fulda S, Gewirtz DA, Green DR, Hansen M, Harper JW, Jaattela M, Johansen T, Juhasz G, Kimmelman AC, Kraft C, Ktistakis NT, Kumar S, Levine B, Lopez-Otin C, Madeo F, Martens S, Martinez J, Melendez A, Mizushima N, Munz C, Murphy LO, Penninger JM, Piacentini M, Reggiori F, Rubinsztein DC, Ryan KM, Santambrogio L, Scorrano L, Simon AK, Simon HU, Simonsen A, Tavernarakis N, Tooze SA, Yoshimori T, Yuan J, Yue Z, Zhong Q, Kroemer G (2017) Molecular definitions of autophagy and related processes. EMBO J 36(13):1811–1836.  https://doi.org/10.15252/embj.201796697 CrossRefPubMedGoogle Scholar
  14. Grattagliano I, Russmann S, Diogo C, Bonfrate L, Oliveira PJ, Wang DQ, Portincasa P (2011) Mitochondria in chronic liver disease. Curr Drug Targets 12(6):879–893CrossRefPubMedGoogle Scholar
  15. Gray MW, Burger G, Lang BF (2001) The origin and early evolution of mitochondria. Genome Biol 2(6):REVIEWS1018CrossRefPubMedPubMedCentralGoogle Scholar
  16. Grimm A, Eckert A (2017) Brain aging and neurodegeneration: from a mitochondrial point of view. J Neurochem 143(4):418–431.  https://doi.org/10.1111/jnc.14037 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Janssen BG, Byun HM, Gyselaers W, Lefebvre W, Baccarelli AA, Nawrot TS (2015) Placental mitochondrial methylation and exposure to airborne particulate matter in the early life environment: an ENVIRONAGE birth cohort study. Epigenetics 10(6):536–544.  https://doi.org/10.1080/15592294.2015.1048412 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Jimenez-Chillaron JC, Nijland MJ, Ascensao AA, Sardao VA, Magalhaes J, Hitchler MJ, Domann FE, Oliveira PJ (2015) Back to the future: transgenerational transmission of xenobiotic-induced epigenetic remodeling. Epigenetics 10(4):259–273.  https://doi.org/10.1080/15592294.2015.1020267 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Kim SJ, Xiao J, Wan J, Cohen P, Yen K (2017) Mitochondrial derived peptides as novel regulators of metabolism. J Physiol 595(21):6613–6621.  https://doi.org/10.1113/JP274472 CrossRefPubMedGoogle Scholar
  20. Kuksal N, Chalker J, Mailloux RJ (2017) Progress in understanding the molecular oxygen paradox - function of mitochondrial reactive oxygen species in cell signaling. Biol Chem 398(11):1209–1227.  https://doi.org/10.1515/hsz-2017-0160 CrossRefPubMedGoogle Scholar
  21. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P (2015) The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 21(3):443–454.  https://doi.org/10.1016/j.cmet.2015.02.009 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Lee C, Kim KH, Cohen P (2016) MOTS-c: a novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med 100:182–187.  https://doi.org/10.1016/j.freeradbiomed.2016.05.015 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Matilainen O, Quiros PM, Auwerx J (2017) Mitochondria and epigenetics - crosstalk in homeostasis and stress. Trends Cell Biol 27(6):453–463.  https://doi.org/10.1016/j.tcb.2017.02.004 CrossRefPubMedGoogle Scholar
  24. McWilliams TG, Muqit MM (2017) PINK1 and Parkin: emerging themes in mitochondrial homeostasis. Curr Opin Cell Biol 45:83–91.  https://doi.org/10.1016/j.ceb.2017.03.013 CrossRefPubMedGoogle Scholar
  25. Nadanaciva S, Will Y (2011a) Investigating mitochondrial dysfunction to increase drug safety in the pharmaceutical industry. Curr Drug Targets 12(6):774–782CrossRefPubMedGoogle Scholar
  26. Nadanaciva S, Will Y (2011b) New insights in drug-induced mitochondrial toxicity. Curr Pharm Des 17(20):2100–2112CrossRefPubMedGoogle Scholar
  27. Novielli C, Mando C, Tabano S, Anelli GM, Fontana L, Antonazzo P, Miozzo M, Cetin I (2017) Mitochondrial DNA content and methylation in fetal cord blood of pregnancies with placental insufficiency. Placenta 55:63–70.  https://doi.org/10.1016/j.placenta.2017.05.008 CrossRefPubMedGoogle Scholar
  28. Paharkova V, Alvarez G, Nakamura H, Cohen P, Lee KW (2015) Rat humanin is encoded and translated in mitochondria and is localized to the mitochondrial compartment where it regulates ROS production. Mol Cell Endocrinol 413:96–100.  https://doi.org/10.1016/j.mce.2015.06.015 CrossRefPubMedGoogle Scholar
  29. Peixoto F, Vicente JA, Madeira VM (2003) The herbicide dicamba (2-methoxy-3,6-dichlorobenzoic acid) interacts with mitochondrial bioenergetic functions. Arch Toxicol 77(7):403–409.  https://doi.org/10.1007/s00204-003-0456-9 CrossRefPubMedGoogle Scholar
  30. Pereira CV, Nadanaciva S, Oliveira PJ, Will Y (2012) The contribution of oxidative stress to drug-induced organ toxicity and its detection in vitro and in vivo. Expert Opin Drug Metab Toxicol 8(2):219–237.  https://doi.org/10.1517/17425255.2012.645536 CrossRefPubMedGoogle Scholar
  31. Pollack Y, Kasir J, Shemer R, Metzger S, Szyf M (1984) Methylation pattern of mouse mitochondrial DNA. Nucleic Acids Res 12(12):4811–4824CrossRefPubMedPubMedCentralGoogle Scholar
  32. Rovira-Llopis S, Banuls C, Diaz-Morales N, Hernandez-Mijares A, Rocha M, Victor VM (2017) Mitochondrial dynamics in type 2 diabetes: pathophysiological implications. Redox Biol 11:637–645.  https://doi.org/10.1016/j.redox.2017.01.013 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Saini SK, Mangalhara KC, Prakasam G, Bamezai RNK (2017) DNA Methyltransferase1 (DNMT1) isoform3 methylates mitochondrial genome and modulates its biology. Sci Rep 7(1):1525.  https://doi.org/10.1038/s41598-017-01743-y CrossRefPubMedPubMedCentralGoogle Scholar
  34. Sajnani K, Islam F, Smith RA, Gopalan V, Lam AK (2017) Genetic alterations in Krebs cycle and its impact on cancer pathogenesis. Biochimie 135:164–172.  https://doi.org/10.1016/j.biochi.2017.02.008 CrossRefPubMedGoogle Scholar
  35. Salminen A, Kauppinen A, Hiltunen M, Kaarniranta K (2014) Krebs cycle intermediates regulate DNA and histone methylation: epigenetic impact on the aging process. Ageing Res Rev 16:45–65.  https://doi.org/10.1016/j.arr.2014.05.004 CrossRefPubMedGoogle Scholar
  36. Schell JC, Rutter J (2017) Mitochondria link metabolism and epigenetics in haematopoiesis. Nat Cell Biol 19(6):589–591.  https://doi.org/10.1038/ncb3540 CrossRefPubMedGoogle Scholar
  37. Schwarz TL (2013) Mitochondrial trafficking in neurons. Cold Spring Harb Perspect Biol 5(6):a011304.  https://doi.org/10.1101/cshperspect.a011304 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Scialo F, Fernandez-Ayala DJ, Sanz A (2017) Role of mitochondrial reverse electron transport in ROS signaling: potential roles in health and disease. Front Physiol 8:428.  https://doi.org/10.3389/fphys.2017.00428 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Silva AM, Barbosa IA, Seabra C, Beltrao N, Santos R, Vega-Naredo I, Oliveira PJ, Cunha-Oliveira T (2016a) Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity. Food Chem Toxicol 94:148–158.  https://doi.org/10.1016/j.fct.2016.06.001 CrossRefPubMedGoogle Scholar
  40. Silva FS, Simoes RF, Couto R, Oliveira PJ (2016b) Targeting mitochondria in cardiovascular diseases. Curr Pharm Des 22(37):5698–5717CrossRefPubMedGoogle Scholar
  41. Stoccoro A, Siciliano G, Migliore L, Coppede F (2017) Decreased methylation of the mitochondrial D-loop region in late-onset Alzheimer's disease. J Alzheimer's Dis 59(2):559–564.  https://doi.org/10.3233/JAD-170139 CrossRefGoogle Scholar
  42. Tavares MV, Santos MJ, Domingues AP, Pratas J, Mendes C, Simoes M, Moura P, Diogo L, Grazina M (2013) Antenatal manifestations of mitochondrial disorders. J Inherit Metab Dis 36(5):805–811.  https://doi.org/10.1007/s10545-012-9567-x CrossRefPubMedGoogle Scholar
  43. Voigt A, Jelinek HF (2016) Humanin: a mitochondrial signaling peptide as a biomarker for impaired fasting glucose-related oxidative stress. Physiol Rep 4(9):e12796.  https://doi.org/10.14814/phy2.12796 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Wallace DC, Fan W (2010) Energetics, epigenetics, mitochondrial genetics. Mitochondrion 10(1):12–31.  https://doi.org/10.1016/j.mito.2009.09.006 CrossRefPubMedGoogle Scholar
  45. Wilkins HM, Weidling IW, Ji Y, Swerdlow RH (2017) Mitochondria-derived damage-associated molecular patterns in neurodegeneration. Front Immunol 8:508.  https://doi.org/10.3389/fimmu.2017.00508 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.CNC – Center for Neuroscience and Cell BiologyUC-Biotech, University of CoimbraCantanhedePortugal

Personalised recommendations