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Houstek 2014 Abstract MiP2014

From Bioblast
Alteration of structure and function of ATP synthase and cytochrome c oxidase by lack of Fo-a and Cox3 subunits caused by mitochondrial DNA 9205delTA mutation.


Houstek J

Mitochondr Physiol Network 19.13 - MiP2014

Hejzlarova K, Kaplanova V, Jesina P, Drahota Z, Nuskova H, Kovarova N, Mracek T, Houstek J (2014)

Event: MiP2014

Mitochondrial disorders due to maternally transmitted dysfunction of ATP synthase are frequently caused by missense mutations in the mtDNA MTATP6 gene. A different type of MTATP6 mutation is represented by a unique 9205delTA microdeletion which disrupts the STOP codon of the MTATP6 gene and affects the cleavage site in the MTATP8/MTATP6/MTCO3 polycistronic transcript. This change interferes with the processing and translation of mRNAs for the ATP6 subunit (Fo-a) of the ATP synthase and Cox3 subunit of the cytochrome c oxidase (Complex IV, CIV). Two cases, described so far, presented strikingly different clinical phenotypes – mild transient lactic acidosis or fatal encephalopathy [1,2]. To gain more insight into the pathogenic mechanism, we prepared 9205delTA cybrids with a mutation load between 50–100% and investigated changes in the structure and function of ATP synthase and CIV.

We found that 9205delTA mutation diminishes the synthesis of both Fo-a and Cox3 proteins, alters the structure but not the content of ATP synthase, decreases the content of CIV and prevents most of the mitochondrial ATP production. The ATP synthase complex was assembled without Fo-a subunit but it was rather labile. It retained ATP hydrolytic activity but was unable to synthesize ATP. The biochemical effects displayed a pronounced threshold effect above 85% of mutation heteroplasmy. Since the relationship between the reduction of subunit Fo-a or Cox3 content and functional impairment was linear, the threshold effect originated primarily from a gene-protein level.

β€’ O2k-Network Lab: CZ Prague Houstek J

Labels: MiParea: mtDNA;mt-genetics, mt-Medicine, Patients 

Enzyme: Complex IV;cytochrome c oxidase 

Event: A1, Poster  MiP2014 


Dep Bioenergetics, Inst Physiol AS CR v.v.i., Prague, Czech Republic. -

References and acknowledgements

Supported by the Grant Agency of the Czech Republic (14-368046) and Ministry of education, youth and sports of the Czech Republic (LL1204).

  1. Seneca S, Abramowicz M, Lissens W, Muller MF, Vamos E, de Meirleir L (1996) A mitochondrial DNA microdeletion in a newborn girl with transient lactic acidosis. J Inherit Metab Dis 19: 115-8.
  2. Jesina P, Tesarova M, Fornuskova D, Vojtiskova A, Pecina P, Kaplanova V, Hansikova H, Zeman J, Houstek J (2004) Diminished synthesis of subunit a (ATP6) and altered function of ATP synthase and cytochrome c oxidase due to the mtDNA 2 bp microdeletion of TA at positions 9205 and 9206. Biochem J 383: 561-71.