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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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Mitochondrial transfer disrupts mTORC1/Akt signaling modulating biogenesis and respiration

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