Mitochondrial DNA: Fate of the Paternal Mitochondrial Genome


The mitochondrial genome encodes key proteins of the electron transfer chain, which generates the vast majority of cellular adenosine triphosphate through oxidative phosphorylation. This genome is normally transmitted to subsequent generations through the oocyte and is thus maternally inherited. Sperm mitochondrial deoxyribonucleic acid (mtDNA) is normally eliminated early during embryonic development, but this tends to be species specific. There are several interconnected mechanisms that could account for its elimination, including ubiquitin depended proteolysis, mtDNA digestion by a dedicated endonuclease and whole organelle autophagy/mitophagy. The elimination of sperm mitochondrial DNA is essential for the functional integrity of the embryo, and for the health, fitness and fertility of the offspring. Sperm mtDNA appears to harbour a large number of defects, whereas maternally inherited mitochondrial DNA rearrangements appear to be transmitted at a very low frequency. However, there is an increasing number of assisted reproductive technologies and therapies that could lead to the transmission of paternal/foreign mitochondrial DNA and this requires significant investigation.

Key Concepts

  • Mitochondria are semi‐autonomous energy‐producing organelles with their own genome (mitochondrial DNA/mtDNA) and transcriptional and translational machinery.
  • Mitochondrial health influences fitness, health and fertility in humans and animals.
  • In most animals and in humans, mitochondria and mitochondrial genomes are inherited clonally, from mother (the concept of ‘mitochondrial Eve’), though exceptions exist.
  • Paternal mitochondria enter the oocyte at fertilisation but are eliminated soon thereafter by the ooplasmic autophagy/mitophagy machinery.
  • Sperm‐borne (paternal) mitochondria are predestined for proteolysis and mitophagy as they are tagged with the recycling marker ubiquitin during the haploid phase of spermatogenesis.
  • Elimination of paternal mitochondria is essential for an individual's health as it prevents the transmission of harmful mtDNA mutations and deletions.
  • Paternal mitochondrial heteroplasmy caused by the leakage/recycling failure of sperm mitochondria after fertilisation has been associated with mitochondrial disease in humans.
  • Some assisted reproductive therapies (ART) such as intracytoplasmic sperm injection (ICSI) may be liable to convey paternal mitochondrial leakage, though there is no consistent screening for it ART children.

Keywords: mitochondria; mtDNA; inheritance; heteroplasmy; sperm; fertilisation; autophagy; ubiquitin; proteasome

Figure 1. The mammalian mitochondrial genome. MtDNA is a double‐stranded closed circular genome consisting of a heavy (H) and light (L) strand. The H strand encodes 12 subunits of the electron transfer chain: ND1, ND2, ND3, ND4, ND4L and ND5 (complex I; NADH dehydrogenase); CYTB (complex III); COXI, COXII and COXIII (complex IV); and ATP6 and ATP8 (ATP synthase; complex V). It also encodes the 16‐S and 12‐S ribosomal ribonucleic acids (rRNAs) and 14 transfer RNAs (tRNAs). The L strand encodes one subunit, ND6 (Complex I) and 8 tRNAs. The mtDNA has one noncoding region, the displacement loop (D‐loop), which is the genome's control region that acts as a regulatory region for interaction with the chromosomally encoded transcription and replication factors. It also contains the origin of heavy strand of replication (OH), the heavy (H) and light strand promoters (LSP) and two hypervariable regions, which discriminate between maternal lineages. The origin of light strand replication (OL) is located two‐thirds of the way around the genome. Reproduced with permission from St John . © Springer Nature.
Figure 2. Replication of mtDNA. Replication of the mitochondrial genome is initiated by TFAM, which generates an RNA–DNA hybrid primer. Replication then proceeds from the origin of heavy strand replication (OH). The double‐stranded mitochondrial genome is unwound by TWINKLE, the mtDNA‐specific helicase. The separated strands are bound by mitochondrial single‐stranded binding proteins (mtSSB) to prevent reannealing prior to completion of replication. The mtDNA polymerase complex comprises the catalytic subunit (POLGA) and two supporting processivity subunits (POLGB). Proofreading is undertaken by the 3'–5' exonuclease activity within POLGA. Reproduced with permission from St John . © Springer Nature.
Figure 3. mtDNA copy number during spermatogenesis and spermiogenesis. Spermatogenesis has some requirement for mtDNA in order to generate ATP for motility. Differentiating spermatogonia initially expand their mtDNA copy number then reduce it quite considerably as they differentiate into spermatocytes and spermatids to ensure that as few copies as possible enter the oocyte at fertilisation. Reproduced with permission from St John . © John Wiley and Sons.
Figure 4. mtDNA copy number during oogenesis. Mammals inherit mtDNA from the population of mtDNA present in the oocyte at fertilisation. At fertilisation, the mature metaphase‐II oocyte has 4 200 000 copies of mtDNA and these are derived from approximately 200 copies that are present in primordial germ cells, which are the first identifiable germ cells. In the mouse, these are laid at embryonic day 6.5. Oocytes require 4 200 000 copies of mtDNA to mediate the process of fertilisation and those oocytes that have 5 200 000 copies of mtDNA often fail to fertilise or arrest during development. Reproduced with permission from St John . © John Wiley and Sons.


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St John, Justin C, and Sutovsky, Peter(Aug 2019) Mitochondrial DNA: Fate of the Paternal Mitochondrial Genome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006165.pub3]