Molecular Basis for Maternal Inheritance of Human Mitochondrial DNA

Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization1, 2. The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy3, 4. However, whether these mechanisms play a decisive role in paternal mtDNA elimination has been disputed5, 6. We found that mitochondria in human spermatozoa are devoid of mtDNA and lack mitochondrial transcription factor A (TFAM), the major nucleoid protein required to protect, maintain, and transcribe mtDNA. During spermatogenesis, sperm cells express an isoform of TFAM, which retains the mitochondrial pre-sequence, ordinarily removed upon mitochondrial import. Phosphorylation of this pre-sequence prevents mitochondrial import and directs TFAM to the spermatozoon nucleus. TFAM re-localization from the mitochondria of spermatogonia to the spermatozoa nucleus directly correlates with the elimination of mitochondrial DNA, thereby explaining maternal inheritance in this species.National Institutes of Health grant R35 GM131832 (DT). PID2020-115091RB-I00, MCIN/AEI/10.13039/501100011033 Spain (RT). PI2020/09-4, CIBERNED, Instituto de Salud Carlos III (ISCIII) Spain (RT).N