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Mechanisms of mtDNA segregation and mitochondrial signalling in cells with the pathogenic A3243G mutation

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Mechanisms of mtDNA segregation and mitochondrial signalling in cells with the pathogenic A3243G mutation

Jahangir Tafrechi, R.S.

Citation

Jahangir Tafrechi, R. S. (2008, June 5). Mechanisms of mtDNA segregation and

mitochondrial signalling in cells with the pathogenic A3243G mutation. Retrieved from https://hdl.handle.net/1887/12961

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/12961

Note: To cite this publication please use the final published version (if applicable).

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MECHANISMS OF mtDNA SEGREGATION AND MITOCHONDRIAL SIGNALING IN CELLS WITH THE PATHOGENIC A3243G MUTATION

Proefschrift

ter verkrijging van

de graad van Doctor aan de Universiteit van Leiden,

op gezag van de Rector Magnificus Prof. Mr. P. F. van der Heijden, volgens besluit van het College der Promoties

te verdedigen op 5 juni 2008 klokke 15:00 uur

door

Roshan Sakineh Jahangir Tafrechi geboren te Heemstede

in 1974

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P

romotiecommissie

Promotores Prof. Dr. A. K. Raap

Prof. Dr. J. A. Maassen

Co-Promotor Dr. G. M. C. Janssen

Referent Dr. H. J. M. Smeets (Universiteit van Maastricht) Overige leden Prof. Dr. P. de Knijff

Prof. Dr. L. H. F. Mullenders

The cover shows electron microscopic images of mitochondria in the cells used in this thesis. Wild type cells show mitochondria with linear cristae and mutant cells show mitochondria with aberrant circular and concentric ring patterns.

The images were taken by courtesy of the Section Electron Microscopy.

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Contents Page

Chapter 1: General introduction 5 Chapter 2: Single cell A3243G mitochondrial DNA mutation load 19

assays for mtDNA segregation analyses

Chapter 3: Suppressed and quantal mtDNA segregation in 33 heteroplasmic cell cultures

Chapter 4: Distinct nuclear gene expression profiles in cells with 47 mtDNA depletion and homoplasmic A3243G mutation Chapter 5: Effects of mtDNA variants on the nuclear transcription 61

profile and the cytosolic protein synthesis machinery Chapter 6: General discussion 77

Summary 87

Samenvatting 91

Samenvatting voor de leek 95 CurriculumVitae with list of publication 97

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