Inhibition of mitochondrial fission favours mutant over wild-type mitochondrial DNA.

TitleInhibition of mitochondrial fission favours mutant over wild-type mitochondrial DNA.
Publication TypeJournal Article
Year of Publication2009
AuthorsMalena, A, Loro, E, Di Re, M, Holt, IJ, Vergani, L
JournalHum Mol Genet
Volume18
Issue18
Pagination3407-16
Date Published2009 Sep 15
ISSN1460-2083
KeywordsBase Sequence, Cell Line, Tumor, DNA, Mitochondrial, Down-Regulation, Gene Dosage, GTP Phosphohydrolases, Humans, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Molecular Sequence Data, Mutation
Abstract

Biased segregation of mitochondrial DNA variants has been widely documented, but little was known about its molecular basis. We set out to test the hypothesis that altering the balance between mitochondrial fusion and fission could influence the segregation of mutant and wild-type mtDNA variants, because it would modify the number of organelles per cell. Therefore human cells heteroplasmic for the pathological A3243G mitochondrial DNA mutation were transfected with constructs designed to silence Drp1 or hFis1, whose gene products are required for mitochondrial fission. Drp1 and hFis1 gene silencing were both associated with increased levels of mutant mitochondrial DNA. Thus, the extent of the mitochondrial reticular network appears to be an important factor in determining mutant load. The fact that the level of mutant and wild-type mitochondrial DNA can be manipulated by altering the expression of nuclear encoded factors involved in mitochondrial fission suggests new interventions for mitochondrial DNA disorders.

DOI10.1093/hmg/ddp281
Alternate JournalHum. Mol. Genet.
Citation Key10.1093/hmg/ddp281
PubMed ID19561330
Grant ListMC_U105663140 / / Medical Research Council / United Kingdom