Effect of experimental complex III deficiency on respiratory chain assembly and function

Detta är en avhandling från Paediatrics, Faculty of Medicine, Lund University

Sammanfattning: The assembly of respiratory chain complexes in the mitochondrial inner membrane requires specific factors. Once assembled to form a mature functional complex, complex III (CIII) is a dimer consisting of two monomers, each with eleven subunits. To date, seven assembly factors for CIII are known, of which BCS1L incorporates the Rieske iron-sulfur protein (RISP) in the last stage of the assembly. The most severe CIII deficiency, due to a mutation in BCS1L (homozygous c.232A>G), is GRACILE syndrome (growth restriction, aminoaciduria, cholestasis, iron accumulation, lactic acidosis, and early death, MIM 603358).
To clarify the mechanisms of BCS1L-related disorders, especially possible changes in supercomplex formation, the specific aims of this thesis were to investigate CIII assembly and supercomplexes in a mouse model harboring the Bcs1l mutation c.232A>G. In homozygotes, the mutation results in a progressive CIII deficiency mimicking the human syndrome. To elucidate the role of the RISP subunit, wild type mice were exposed to CIII inhibition with myxothiazol administration.
The result showed that complex I can interact with pre-complex III and form a supercomplex in the absence of mature holo-CIII. When RISP was inhibited in CIII by myxothiazol, supercomplex formation was not affected. The supercomplex assembly factor I (Scafi) is required for inclusion of complex IV in supercomplexes. Liver metabolomics of the progressive CIII deficiency in homozygous mice showed a starvation-like situation and signs of oxidative stress at the end stage of the disease.
In conclusion, supercomplex formation is a dynamic process that in the case of mutations in BCS1L or supercomplex assembly factor I is modified to incorporate the pre-complex of CIII and an increased amount of complex I to maintain respiratory chain function.

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