Organismal Dynamics

Gene expression and development in Coenzyme Q deficiency: a model to establish the origin of this mitochondrial disease

Dr Daniel José Moreno Fernández-Ayala

 Researcher

Summary 

CoQ deficiencies are a group of heterogeneous mitochondrial diseases characterized by a depletion in the CoQ level. CoQ is synthesized inside mitochondria where it participates in oxidative phosphorylation to generate ATP. Many genes are directly or indirectly involved in the mitochondrial synthesis of CoQ. It can be caused by defects in genes that are part of the CoQ10 synthesis complex or in its regulation inside mitochondria (primary deficiency), or as a secondary effect due to the alteration of other mitochondrial functions not directly involved in CoQ10 synthesis.

Any of these mutations induce depletion of CoQ levels, and cells retrain their metabolism to survive under defective mitochondria thanks to epigenetic modifications and changes in gene expression to generate a specific transcriptome for survival.

Human primary cell cultures obtained from patients with CoQ deficiencies allowed us to study these alterations in vitro, whereas animal models (mouse and fruit flies) permit us to study how an organism develops under CoQ depletion and how it ages prematurely.

We specifically studied muscle development in a mouse model of CoQ deficiency and characterized their defective mitochondria. Also, we are establishing different strategies to treat CoQ deficiency using these animal models.

We purify live mitochondria from muscle and study the differentiation process of muscle stem cells. 

https://www.jove.com/v/63336/isolation-mitochondria-from-mouse-skeletal-muscle-for-respirometric?language=Spanish

Relevant publications 

 

 

  • Hernández-Camacho JD, Fernández-Ayala DJM, Vicente-García C, Navas-Enamorado I, López-Lluch G, Oliva C, Artuch R, Garcia-Villoria J, Ribes A, de Cabo R, Carvajal JJ, Navas P. Calorie Restriction Rescues Mitochondrial Dysfunction in Adck2-Deficient Skeletal Muscle. Front Physiol. 2022 Jul 14;13:898792. doi: 10.3389/fphys.2022.898792. PMID: 35936917; PMCID: PMC9351392.
  • Hernández-Camacho JD, Vicente-García C, Sánchez-Cuesta A, Fernandez-Ayala DJM, Carvajal JJ, Navas P. Isolation of Mitochondria from Mouse Skeletal Muscle for Respirometric Assays. J Vis Exp. 2022 Feb 10;(180). doi: 10.3791/63336. PMID: 35225269.
  • Vázquez-Fonseca L, Schaefer J, Navas-Enamorado I, Santos-Ocaña C, Hernández-Camacho JD, Guerra I, Cascajo MV, Sánchez-Cuesta A, Horvath Z, Siendones E, Jou C, Casado M, Gutiérrez P, Brea-Calvo G, López-Lluch G, Fernández-Ayala DJM, Cortés-Rodríguez AB, Rodríguez-Aguilera JC, Matté C, Ribes A, Prieto-Soler SY, Dominguez-Del-Toro E, Francesco AD, Aon MA, Bernier M, Salviati L, Artuch R, Cabo R, Jackson S, Navas P. ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency. J Clin Med. 2019 Sep 2;8(9):1374. doi: 10.3390/jcm8091374. PMID: 31480808; PMCID: PMC6780728.
  • Rodríguez-Aguilera JC, Cortés AB, Fernández-Ayala DJ, Navas P. Biochemical Assessment of Coenzyme Q10 Deficiency. J Clin Med. 2017 Mar 5;6(3):27. doi: 10.3390/jcm6030027. PMID: 28273876; PMCID: PMC5372996.
  • Scialò F, Sriram A, Fernández-Ayala D, Gubina N, Lõhmus M, Nelson G, Logan A, Cooper HM, Navas P, Enríquez JA, Murphy MP, Sanz A. Mitochondrial ROS Produced via Reverse Electron Transport Extend Animal Lifespan. Cell Metab. 2016 Apr 12;23(4):725-34. doi: 10.1016/j.cmet.2016.03.009. PMID: 27076081; PMCID: PMC4835580.
  • Fernández-Ayala DJ, Guerra I, Jiménez-Gancedo S, Cascajo MV, Gavilán A, Dimauro S, Hirano M, Briones P, Artuch R, De Cabo R, Salviati L, Navas P. Survival transcriptome in the coenzyme Q10 deficiency syndrome is acquired by epigenetic modifications: a modeling study for human coenzyme Q10 deficiencies. BMJ Open. 2013 Mar 25;3(3):e002524. doi: 10.1136/bmjopen-2012-002524. PMID: 23533218; PMCID: PMC3612821.
  • Fernández-Ayala DJ, Chen S, Kemppainen E, O’Dell KM, Jacobs HT. Gene expression in a Drosophila model of mitochondrial disease. PLoS One. 2010 Jan 6;5(1):e8549. doi: 10.1371/journal.pone.0008549. PMID: 20066047; PMCID: PMC2798955.
  • Fernandez-Ayala DJ, Sanz A, Vartiainen S, Kemppainen KK, Babusiak M, Mustalahti E, Costa R, Tuomela T, Zeviani M, Chung J, O’Dell KM, Rustin P, Jacobs HT. Expression of the Ciona intestinalis alternative oxidase (AOX) in Drosophila complements defects in mitochondrial oxidative phosphorylation. Cell Metab. 2009 May;9(5):449-60. doi: 10.1016/j.cmet.2009.03.004. PMID: 19416715.
  • Fernández-Ayala DJ, Brea-Calvo G, López-Lluch G, Navas P. Coenzyme Q distribution in HL-60 human cells depends on the endomembrane system. Biochim Biophys Acta. 2005 Jul 30;1713(2):129-37. doi: 10.1016/j.bbamem.2005.05.010. PMID: 15993380.
  • Fernández-Ayala DJ, López-Lluch G, García-Valdés M, Arroyo A, Navas P. Specificity of coenzyme Q10 for a balanced function of the respiratory chain and endogenous ubiquinone biosynthesis in human cells. Biochim Biophys Acta. 2005 Jan 7;1706(1-2):174-83. doi: 10.1016/j.bbabio.2004.10.009. PMID: 15620378.

Lab members & collaborators

Lab members

Group leader

Daniel Jose Moreno Fernandez-Ayala
Tlf. +34 954978184 (interno UPO: 68184)
e-mail: dmorfer@upo.es

Lab technician

Ana Mª Sánchez Cuesta

Estudiante de doctorado

Juan Diego Hernández Camacho (jdhercam@upo.es)

Collaborators

Jaime Carvajal Garcia-Valdecasas (CABD-CSIC/UPO, Sevilla)
Alberto Sanz Montero (School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom)