An alternative model for maternal mtDNA inheritance

Abstract

arising from W. Lee et al. Nature Genetics https://doi.org/10.1038/s41588-023-01505-9 (2023)

The exact mechanism preventing paternal mitochondrial DNA (mtDNA) inheritance in humans remains unresolved. In their recent report, ‘Molecular basis for maternal inheritance of human mitochondrial DNA’, Lee et al. propose that this process is controlled by phosphorylation of the mitochondrial transcription factor A (TFAM) on two serine residues located in the matrix targeting sequence (MTS), which blocks this protein’s mitochondrial import, thus uncoating mtDNA and exposing it to attack and destruction by unspecified mitochondrial nuclease(s), which prevents paternal mtDNA from entering the oocyte during fertilization. We argue that the experimental evidence presented in the article is inconclusive and also supports an alternative possibility: that mtDNA turnover following the loss of expression of key mtDNA replication proteins might be responsible. Therefore, additional experimentation is needed to resolve the two competing mechanisms that align with the experimental data presented by Lee et al.