MiP2005: Session 10 - Young Investigator Presentation
Mitochondrial Physiology Network 10.9: 115-116 (2005) - download pdf
Cytochrome c oxidase assembly defects.
Petr Pecina1, Z Drahota1, M Vrbacký1, C Dell'Agnello2, M Zeviani2, J Houštěk1
1Institute of Physiology and Center for Integrated Genomics, Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20 Prague, Czech Republic; 2Unit of Molecular Neurogenetics, National Neurological Institute, 'Carlo Besta', Milan, Italy - firstname.lastname@example.org
Mutations in SURF1, the cytochrome c oxidase (COX)-specific assembly factor, are the primary cause of Leigh syndrome associated with COX deficiency (LSCOX), one of the most frequent mitochondrial disorder with fatal consequences . The Surf1p absence in LSCOX patient fibroblasts leads to severe reduction of COX holoenzyme and accumulation of COX assembly intermediates. Our previous studies showed that such deficiency manifests in decreased stability of the enzyme, impaired proton-pumping ability of COX, and decreased affinity of the enzyme for oxygen [2, 3]. We suggested that these functional changes were due to altered properties of the COX assembly intermediates [2, 3].
Recently, we explored our studies in the SURF1 knock-out mice model of LSCOX . In mitochondria isolated from tissues of homozygous SURF1 -/- mice we observed similar functional alterations as in patient fibroblasts, e.g. decreased affinity of COX to oxygen and release of the enzyme downregulation. These changes, however, were not accompanied by the accumulation of COX assembly intermediates, only severe reduction of the holoenzyme content was found. Using high-resolution BN-PAGE and 2D-PAGE techniques and the SURF1 knock-out mice model we aim to further resolve whether the functional manifestations of the COX assembly defect are due to: (i) accumulation of intermediates with altered functional properties; (ii) change in subunit composition of the COX holoenzyme that has not been so far recognized due to low resolution of BN-PAGE, i. e. absence of one or several small nuclear-encoded subunits; and (iii) decreased content of otherwise structuraly and functionaly normal COX.
1. Tiranti V, Hoertnagel K, Carrozzo R, Galimberti C, Munaro M, Granatiero M, Zelante L, Gasparini P, Marzella R, Rocchi M, Bayona-Bafaluy MP, Enriquez JA, Uziel G, Bertini E, Dionisi-Vici C, Franco B, Meitinger T, Zeviani M (1998) Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet. 63: 1609-1621.
2. Pecina P, Capkova M, Chowdhury SK, Drahota Z, Dubot A, Vojtiskova A, Hansikova H, Houst'kova H, Zeman J, Godinot C, Houstek J (2003) Functional alteration of cytochrome c oxidase by SURF1 mutations in Leigh syndrome. Biochim. Biophys. Acta. 1639: 53-63.
3. Pecina P, Gnaiger E, Zeman J, Pronicka E, Houstek J (2004) Decreased affinity for oxygen of cytochrome-c oxidase in Leigh syndrome caused by SURF1 mutations. Am. J. Physiol. Cell Physiol. 287: C1384-C1388.
4. Agostino A, Invernizzi F, Tiveron C, Fagiolari G, Prelle A, Lamantea E, Giavazzi A, Battaglia G, Tatangelo L, Tiranti V, Zeviani M (2003) Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice. Hum. Mol. Genet. 12: 399-413.