| Full text | |
| Author(s): Show less - |
Zhang, Haixin
[1, 2]
;
Esposito, Marco
[3, 4]
;
Pezet, Mikael G.
[1, 2]
;
Aryaman, Juvid
[3]
;
Wei, Wei
[1, 2]
;
Klimm, Florian
[1, 2, 3]
;
Calabrese, Claudia
[1, 2]
;
Burr, Stephen P.
[1, 2]
;
Macabelli, Carolina H.
[5]
;
Viscomi, Carlo
[1, 2]
;
Saitou, Mitinori
[6, 7]
;
Chiaratti, Marcos R.
[5]
;
Stewart, James B.
[8, 9]
;
Jones, Nick
[3, 4]
;
Chinnery, Patrick F.
[1, 2]
Total Authors: 15
|
| Affiliation: | [1] Univ Cambridge, Sch Clin Med, Dept Clin Neurosci, Cambridge Biomed Campus, Cambridge - England
[2] Univ Cambridge, MRC, Mitochondrial Biol Unit, Cambridge Biomed Campus, Cambridge - England
[3] Imperial Coll, EPSRC Ctr Math Precis Healthcare, Dept Math, London - England
[4] Imperial Coll, Leverhulme Ctr Cellular Bion, London - England
[5] Univ Fed Sao Carlos, Dept Genet & Evolucao, BR-13565905 Sao Carlos - Brazil
[6] Kyoto Univ, Grad Sch Med, Dept Anat & Cell Biol, Sakyo Ku, Yoshida Konoe Cho, Kyoto 6068501 - Japan
[7] JST, ERATO, Sakyo Ku, Yoshida Konoe Cho, Kyoto 6068501 - Japan
[8] Max Planck Inst Biol Ageing, D-50931 Cologne - Germany
[9] Newcastle Univ, Fac Med Sci, Wellcome Ctr Mitochondrial Res, Biosci Inst, Newcastle Upon Tyne, Tyne & Wear - England
Total Affiliations: 9
|
| Document type: | Journal article |
| Source: | SCIENCE ADVANCES; v. 7, n. 50 DEC 2021. |
| Web of Science Citations: | 0 |
| Abstract | |
Heteroplasmic mitochondrial DNA (mtDNA) mutations are a common cause of inherited disease, but a few recurrent mutations account for the vast majority of new families. The reasons for this are not known. We studied heteroplasmic mice transmitting m.5024C>T corresponding to a human pathogenic mutation. Analyzing 1167 mother-pup pairs, we show that m.5024C>T is preferentially transmitted from low to higher levels but does not reach homoplasmy. Single-cell analysis of the developing mouse oocytes showed the preferential increase in mutant over wild- type mtDNA in the absence of cell division. A similar inheritance pattern is seen in human pedigrees transmitting several pathogenic mtDNA mutations. In m.5024C>T mice, this can be explained by the preferential propagation of mtDNA during oocyte maturation, counterbalanced by purifying selection against high heteroplasmy levels. This could explain how a disadvantageous mutation in a carrier increases to levels that cause disease but fails to fixate, causing multigenerational heteroplasmic mtDNA disorders. (AU) | |
| FAPESP's process: | 17/04372-0 - Mitochondrial DNA: mechanisms for genome integrity maintenance and impact on disease |
| Grantee: | Nadja Cristhina de Souza Pinto |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 16/07868-4 - Effect of the mitofusins knockout on the inheritance of deleterious mitochondrial DNA in mouse embryonic fibroblasts |
| Grantee: | Carolina Habermann Macabelli |
| Support Opportunities: | Scholarships in Brazil - Doctorate |