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

Davoudi, Mina LU (2014) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2014:125.
Abstract (Swedish)
Popular Abstract in Swedish

Kroppens förmåga att omvandla matens energi till energi som kan användas i organen sker i små organeller som finns i alla kroppens celler, mitokondrierna. Avvikelser i mitokondrierna förorsakar därför ofta svåra sjukdomar. GRACILE syndrom är en medfödd mitokondriell sjukdom, som leder till svår tillväxthämning, problem med ämnesomsättningen och tidig död. Det finns ingen behandling för dessa barn.

Sjukdomen beror på en mutation i BCS1L genen. Detta leder till ett förändrat BCS1L protein, som inte längre kan bygga ihop komplex III i andningskedjan.

Andningskedjan finns i mitokondrierna och har till uppgift att skapa cellernas energi, ATP. Andningskedjan består av fyra stora... (More)
Popular Abstract in Swedish

Kroppens förmåga att omvandla matens energi till energi som kan användas i organen sker i små organeller som finns i alla kroppens celler, mitokondrierna. Avvikelser i mitokondrierna förorsakar därför ofta svåra sjukdomar. GRACILE syndrom är en medfödd mitokondriell sjukdom, som leder till svår tillväxthämning, problem med ämnesomsättningen och tidig död. Det finns ingen behandling för dessa barn.

Sjukdomen beror på en mutation i BCS1L genen. Detta leder till ett förändrat BCS1L protein, som inte längre kan bygga ihop komplex III i andningskedjan.

Andningskedjan finns i mitokondrierna och har till uppgift att skapa cellernas energi, ATP. Andningskedjan består av fyra stora proteinkomplex. Om BCS1L proteinet inte kan bygga ihop komplex III blir andningskedjan mindre effektiv och kan inte längre producera tillräckligt ATP.

För att förstå komplex III bättre och på sikt kunna hjälpa patienter med mitokondriesjukdom p.g.a. minskad komplex III funktion har vi skapat en musmodell där vi kan undersöka hur komplexen och deras samspel i andningskedjan påverkas av en mutation i BCS1L.

Mutation i motsvarande gen i möss leder till snarlik sjukdomsbild som de nyfödda barnen har. Genom att isolera mitokondrier och membranproteiner från muslever analyserade vi proteinsammansättningen i sjuka möss och jämförde med kontroller. Resultatet visade att mutationen leder till att ett bristfälligt ihop byggt komplex III kan delta i formation av sammansatta komplex, så kallade superkomplex, och på så sätt kompensera för bristen. Vi studerade två musstammar med olika superkomplex och visade att variationen i superkomplexstrukturen inte hade betydelse för mössens överlevnad.

Våra studier visade att andningskedjans komplex kan bilda fungerande kombinationer på ett dynamiskt sätt om komplex III har en avvikande struktur och på så sätt upprätthålla andningskedjans funktion åtminstone en tid. (Less)
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Kastaniotis, Alexander, University of Oulu
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2014:125
pages
64 pages
publisher
Paediatrics, Faculty of Medicine, Lund University
defense location
Segerfalk Lecture Hall, BMC A10, Sölvegatan 17, Lund.
defense date
2014-10-31 13:00
ISSN
1652-8220
ISBN
978-917619-054-8
language
English
LU publication?
yes
id
0b971da8-cac8-4dbf-9420-9fd0ed62c238 (old id 4696648)
date added to LUP
2014-10-20 16:35:43
date last changed
2016-09-19 08:44:47
@phdthesis{0b971da8-cac8-4dbf-9420-9fd0ed62c238,
  abstract     = {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&gt;G), is GRACILE syndrome (growth restriction, aminoaciduria, cholestasis, iron accumulation, lactic acidosis, and early death, MIM 603358).<br/><br>
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&gt;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.<br/><br>
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.<br/><br>
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.},
  author       = {Davoudi, Mina},
  isbn         = {978-917619-054-8},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {64},
  publisher    = {Paediatrics, Faculty of Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Effect of experimental complex III deficiency on respiratory chain assembly and function},
  volume       = {2014:125},
  year         = {2014},
}