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Mitochondrial transfer disrupts mTORC1/Akt signaling modulating biogenesis and respiration

ABSTRACT: Mitochondrial DNA (mtDNA) mutations are a major cause of maternally-inherited disease and have no treatment. Prevention strategies are critically important, but current clinical approaches are far from satisfactory. Legislation has changed in the UK to permit the development of mitochondrial transfer in human embryos, but major concerns have been raised about the mis-match of nuclear and mtDNA from ‘three parents’, with late sequelae being passed through the germ-line to subsequent generations. Matching donor and recipient mtDNA haplogroups is the proposed solution, but the effects of ‘haplogroup matching’ have not been tested experimentally. Here we show major changes in the cellular transcriptome both between and within the major mtDNA haplogroups when mitochondria are transferred between cells on a fixed nuclear genetic background. Larger differences were seen between phylogenetically related sub-haplogroups J1 and J2 which differ by only six nucleotides, than between the major haplogroups and known pathogenic mtDNA mutations. mtDNA transfer altered key cell signaling pathways, most notably the mTOR/Akt and the inflammatory cascade. This affected mitochondrial biogenesis, oxygen consumption, and ATP synthesis, and was blocked by rapamycin. These findings identify a key mediator in retrograde nuclear-mitochondrial signaling which is sensitive to subtle changes in mtDNA sequence. Given the established role of mTOR in cancer, neurodegeneration, and metabolic disease, this provides a mechanism for the association between inherited mtDNA variants and common late onset diseases, and demonstrates unexpected and dramatic effects of mitochondrial transfer not corrected by close haplogroup matching.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74009 | GEO | 2023/06/07

SECONDARY ACCESSION(S): PRJNA298735

REPOSITORIES: GEO

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Project description:Sakha M-bM-^@M-^S an area connecting South and Northeast Siberia M-bM-^@M-^S is significant for understanding the history of peopling of Northeast Eurasia and the Americas. Previous studies have shown a genetic contiguity between Siberia and East Asia and the key role of South Siberia in the colonization of Siberia. We report the results of a high-resolution phylogenetic analysis of 701 mtDNAs and 318 Y chromosomes from five native populations of Sakha (Yakuts, Evenks, Evens, Yukaghirs and Dolgans) and of the analysis of more than 500,000 autosomal SNPs of 758 individuals from 55 populations, including 40 previously unpublished samples from Siberia. Phylogenetically terminal clades of East Asian mtDNA haplogroups C and D and Y-chromosome haplogroups N1c, N1b and C3, constituting the core of the gene pool of the native populations from Sakha, connect Sakha and South Siberia. Analysis of autosomal SNP data confirms the genetic continuity between Sakha and South Siberia. Maternal lineages D5a2a2, C4a1c, C4a2, C5b1b and the Yakut-specific STR sub-clade of Y-chromosome haplogroup N1c can be linked to a migration of Yakut ancestors, while the paternal lineage C3c was most likely carried to Sakha by the expansion of the Tungusic people. MtDNA haplogroups Z1a1b and Z1a3, present in Yukaghirs, Evens and Dolgans, show traces of different and probably more ancient migration(s). Analysis of both haploid loci and autosomal SNP data revealed only minor genetic components shared between Sakha and the extreme Northeast Siberia. Although the major part of West Eurasian maternal and paternal lineages in Sakha could originate from recent admixture with East Europeans, mtDNA haplogroups H8, H20a and HV1a1a, as well as Y-chromosome haplogroup J, more probably reflect an ancient gene flow from West Eurasia through Central Asia and South Siberia. Our high-resolution phylogenetic dissection of mtDNA and Y-chromosome haplogroups as well as analysis of autosomal SNP data suggests that Sakha was colonized by repeated expansions from South Siberia with minor gene flow from the Lower Amur/Southern Okhotsk region and/or Kamchatka. The minor West Eurasian component in Sakha attests to both recent and ongoing admixture with East Europeans and an ancient gene flow from West Eurasia. 40 samples were analysed with the Illumina platform Human660W-Quad v1.0 and are described herein.

Project description:Sakha – an area connecting South and Northeast Siberia – is significant for understanding the history of peopling of Northeast Eurasia and the Americas. Previous studies have shown a genetic contiguity between Siberia and East Asia and the key role of South Siberia in the colonization of Siberia. We report the results of a high-resolution phylogenetic analysis of 701 mtDNAs and 318 Y chromosomes from five native populations of Sakha (Yakuts, Evenks, Evens, Yukaghirs and Dolgans) and of the analysis of more than 500,000 autosomal SNPs of 758 individuals from 55 populations, including 40 previously unpublished samples from Siberia. Phylogenetically terminal clades of East Asian mtDNA haplogroups C and D and Y-chromosome haplogroups N1c, N1b and C3, constituting the core of the gene pool of the native populations from Sakha, connect Sakha and South Siberia. Analysis of autosomal SNP data confirms the genetic continuity between Sakha and South Siberia. Maternal lineages D5a2a2, C4a1c, C4a2, C5b1b and the Yakut-specific STR sub-clade of Y-chromosome haplogroup N1c can be linked to a migration of Yakut ancestors, while the paternal lineage C3c was most likely carried to Sakha by the expansion of the Tungusic people. MtDNA haplogroups Z1a1b and Z1a3, present in Yukaghirs, Evens and Dolgans, show traces of different and probably more ancient migration(s). Analysis of both haploid loci and autosomal SNP data revealed only minor genetic components shared between Sakha and the extreme Northeast Siberia. Although the major part of West Eurasian maternal and paternal lineages in Sakha could originate from recent admixture with East Europeans, mtDNA haplogroups H8, H20a and HV1a1a, as well as Y-chromosome haplogroup J, more probably reflect an ancient gene flow from West Eurasia through Central Asia and South Siberia. Our high-resolution phylogenetic dissection of mtDNA and Y-chromosome haplogroups as well as analysis of autosomal SNP data suggests that Sakha was colonized by repeated expansions from South Siberia with minor gene flow from the Lower Amur/Southern Okhotsk region and/or Kamchatka. The minor West Eurasian component in Sakha attests to both recent and ongoing admixture with East Europeans and an ancient gene flow from West Eurasia.

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Mitochondrial transfer disrupts mTORC1/Akt signaling modulating biogenesis and respiration

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