A cytoplasmic suppressor of a nuclear mutation affecting mitochondrial functions in Drosophila

Chen, S., Oliveira, M. T., Sanz, A., Kemppainen, E., Fukuoh, A., Schlicht, B., Kaguni, L. S. and Jacobs, H. T. (2012) A cytoplasmic suppressor of a nuclear mutation affecting mitochondrial functions in Drosophila. Genetics, 192(2), pp. 483-493. (doi:10.1534/genetics.112.143719) (PMID:22851652) (PMCID:PMC3454878)

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Abstract

Phenotypes relevant to oxidative phosphorylation (OXPHOS) in eukaryotes are jointly determined by nuclear and mitochondrial DNA (mtDNA). Thus, in humans, the variable clinical presentations of mitochondrial disease patients bearing the same primary mutation, whether in nuclear or mitochondrial DNA, have been attributed to putative genetic determinants carried in the other genome, though their identity and the molecular mechanism(s) by which they might act remain elusive. Here we demonstrate cytoplasmic suppression of the mitochondrial disease-like phenotype of the Drosophila melanogaster nuclear mutant tko25t, which includes developmental delay, seizure sensitivity, and defective male courtship. The tko25t strain carries a mutation in a mitoribosomal protein gene, causing OXPHOS deficiency due to defective intramitochondrial protein synthesis. Phenotypic suppression was associated with increased mtDNA copy number and increased mitochondrial biogenesis, as measured by the expression levels of porin voltage dependent anion channel and Spargel (PGC1α). Ubiquitous overexpression of Spargel in tko25t flies phenocopied the suppressor, identifying it as a key mechanistic target thereof. Suppressor-strain mtDNAs differed from related nonsuppressor strain mtDNAs by several coding-region polymorphisms and by length and sequence variation in the noncoding region (NCR), in which the origin of mtDNA replication is located. Cytoplasm from four of five originally Wolbachia-infected strains showed the same suppressor effect, whereas that from neither of two uninfected strains did so, suggesting that the stress of chronic Wolbachia infection may provide evolutionary selection for improved mitochondrial fitness under metabolic stress. Our findings provide a paradigm for understanding the role of mtDNA genotype in human disease.

Item Type:Articles
Additional Information:This work was supported by funding from the Academy of Finland, Tampere University Hospital Medical Research Fund, the Sigrid Juselius Foundation, European Research Council, European Molecular Biology Organization, and National Institutes of Health (grant GM45295).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sanz Montero, Professor Alberto
Authors: Chen, S., Oliveira, M. T., Sanz, A., Kemppainen, E., Fukuoh, A., Schlicht, B., Kaguni, L. S., and Jacobs, H. T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Genetics
Publisher:Genetics Society of America
ISSN:0016-6731
ISSN (Online):1943-2631
Copyright Holders:Copyright © 2012 by the Genetics Society of America
First Published:First published in Genetics 192(2):483-493
Publisher Policy:Available freely online through the author-supported open access option

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