Mitochondrial DNA: Fate of the Paternal Mitochondrial Genome

Abstract

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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References

Al Rawi S, Louvet‐Vallee S, Djeddi A, et al. (2011) Postfertilization autophagy of sperm organelles prevents paternal mitochondrial DNA transmission. Science 334: 1144–1147.

Amaral A, Ramalho‐Santos J and St John JC (2007) The expression of polymerase gamma and mitochondrial transcription factor A and the regulation of mitochondrial DNA content in mature human sperm. Human Reproduction 22: 1585–1596.

Andrews RM, Kubacka I, Chinnery PF, et al. (1999) Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nature Genetics 23: 147.

Antelman J, Manandhar G, Yi YJ, et al. (2008) Expression of mitochondrial transcription factor A (TFAM) during porcine gametogenesis and preimplantation embryo development. Journal of Cellular Physiology 217 (2): 529–543.

Aw WC, Garvin MR and Ballard JWO (2019) Exogenous factors may differentially influence the selective costs of mtDNA mutations. Advances in Anatomy, Embryology, and Cell Biology 231: 51–74.

Baklouti‐Gargouri S, Ghorbel M, Ben Mahmoud A, et al. (2013) A novel m.6307A4G mutation in the mitochondrial COXI gene in asthenozoospermic infertile men. Molecular Reproduction and Development 80: 581–587.

Barzideh J, Scott RJ and Aitken RJ (2012) Analysis of the global methylation status of human spermatozoa and its association with the tendency of these cells to enter apoptosis. Andrologia. DOI: 10.1111/and.12033.

Bibb MJ, Van Etten RA, Wright CT, Walberg MW and Clayton DA (1981) Sequence and gene organization of mouse mitochondrial DNA. Cell 26: 167–180.

Birky CW Jr (1995) Uniparental inheritance of mitochondrial and chloroplast genes: mechanisms and evolution. Proceedings of the National Academy of Sciences of the USA 92: 11331–11338.

Cataldo L, Baig K, Oko R, Mastrangelo MA and Kleene KC (1996) Developmental expression, intracellular localization, and selenium content of the cysteine‐rich protein associated with the mitochondrial capsules of mouse sperm. Molecular Reproduction and Development 45 (3): 320–331.

Clayton DA (1998) Nuclear‐mitochondrial intergenomic communication. BioFactors 7: 203–205.

Cummins JM, Wakayama T and Yanagimachi R (1997) Fate of microinjected sperm components in the mouse oocyte and embryo. Zygote 5: 301–308.

Cummins JM, Jequier AM, Martin R and Mehmet Dand Goldblatt J (1998) Semen levels of mitochondrial DNA deletions in men attending an infertility clinic do not correlate with phenotype. International Journal of Andrology 21: 47–52.

Dada R, Mahfouz RZ, Kumar R, et al. (2011) A comprehensive work up for an asthenozoospermic man with repeated intracytoplasmic sperm injection (ICSI) failure. Andrologia 43: 368–372.

D'Aquila P, Montesanto A, De Rango F, et al. (2019) Epigenetic signature: implications for mitochondrial quality control in human aging. Aging (Albany NY) 11 (4): 1240–1251.

DeLuca SZ and O'Farrell PH (2012) Barriers to male transmission of mitochondrial DNA in sperm development. Developmental Cell 22: 660–668.

Folgero T, Bertheussen K, Lindal S, Torbergsen T and Oian P (1993) Mitochondrial disease and reduced sperm motility. Human Reproduction 8: 1863–1868.

Foury F, Roganti T, Lecrenier N and Purnelle B (1998) The complete sequence of the mitochondrial genome of Saccharomyces cerevisiae. FEBS Letters 440: 325–331.

Ghiselli F, Milani L, Chang PL, et al. (2012) De novo assembly of the Manila clam Ruditapes philippinarum transcriptome provides new insights into expression bias, mitochondrial doubly uniparental inheritance and sex determination. Molecular Biology and Evolution 29: 771–786.

Greber BJ and Ban N (2016) Structure and function of the mitochondrial ribosome. Annual Review of Biochemistry 85: 103–132.

Gyllensten U, Wharton D, Josefsson A and Wilson AC (1991) Paternal inheritance of mitochondrial DNA in mice. Nature 352: 255–257.

He J, Cooper HM and al RA (2012) Human C4orf14 interacts with the mitochondrial nucleoid and is involved in the biogenesis of the small mitochondrial ribosomal subunit. Nucleic Acids Research 40: 6097–6108.

Herbert M and Turnball D (2018) Progress in mitochondrial replacement therapies. Nature Reviews Molecular Cell Biology 19 (2): 71–72. DOI: 10.1038/nrm.2018.3.

Hecht NB, Liem H, Kleene KC, Distel RJ and Ho SM (1984) Maternal inheritance of the mouse mitochondrial genome is not mediated by a loss or gross alteration of the paternal mitochondrial DNA or by methylation of the oocyte mitochondrial DNA. Developmental Biology 102: 452–461.

Hosseinzadeh Colagar A and Karimi F (2014) Large scale deletions of the mitochondrial DNA in astheno, asthenoterato and oligoasthenoterato‐spermic men. Mitochondrial DNA 25 (4): 321–328.

Innocenti P, Morrow EH and Dowling DK (2011) Experimental evidence supports a sex‐specific selective sieve in mitochondrial genome evolution. Science 332: 845–848.

Kao S, Chao HT and Wei YH (1995) Mitochondrial deoxyribonucleic acid 4977‐bp deletion is associated with diminished fertility and motility of human sperm. Biology of Reproduction 52: 729–736.

Kelly RD, Mahmud A, McKenzie M, Trounce IA and St John JC (2012) Mitochondrial DNAcopy number is regulated in a tissue specific manner by DNA methylation of the nuclear‐encoded DNApolymerase gamma A. Nucleic Acids Research 40: 10124–10138.

Kenchington EL, Hamilton L, Cogswell A and Zouros E (2009) Paternal mtDNA and maleness are co‐inherited but not causally linked in mytilid mussels. PLoS One 4: e6976.

Kondo R, Satta Y, Matsuura ET, et al. (1990) Incomplete maternal transmission of mitochondrial DNA in Drosophila. Genetics 126: 657–663.

Kramer P and Bressan P (2019) Mitochondria inspire a lifestyle. Advances in Anatomy, Embryology, and Cell Biology 231: 105–126.

Kraytsberg Y, Schwartz M, Brown TA, et al. (2004) Recombination of human mitochondrial DNA. Science 304: 981.

Kvist L, Martens J, Nazarenko AA and Orell M (2003) Paternal leakage of mitochondrial DNA in the great tit (Parus major). Molecular Biology and Evolution 20: 243–247.

Larsson NG, Garman JD, Oldfors A, Barsh GS and Clayton DA (1996) A single mouse gene encodes the mitochondrial transcription factor A and a testis‐specific nuclear HMG‐box protein. Nature Genetics 13: 296–302.

Lee S, Kim S, Sun X, Lee JH and Cho H (2007) Cell cycledependent mitochondrial biogenesis and dynamics in mammalian cells. Biochemical and Biophysical Research Communications 357: 111–117.

Lestienne P, Reynier P, Chretien MF, et al. (1997) Oligoasthenospermia associated with multiple mitochondrial DNA rearrangements. Molecular Human Reproduction 3: 811–814.

Luo SM, Ge ZJ, Wang ZW, et al. (2013) Unique insights into maternal mitochondrial inheritance in mice. Proceedings of the National Academy of Sciences of the USA 110: 13038–13043.

Luo S, Valencia CA, Zhang J, et al. (2018) Biparental inheritance of mitochondrial DNA in humans. Proceedings of the National Academy of Sciences of the United States of America 115 (51): 13039–13044.

Marchington DR, Scott Brown MS, Lamb VK, et al. (2002) No evidence for paternal mtDNA transmission to offspring or extra‐embryonic tissues after ICSI. Molecular Human Reproduction 8: 1046–1049.

Margulis L (1971) The origin of plant and animal cells. American Scientist 59 (2): 230–235.

McFarland R, Taylor RW and Turnbull DM (2007) Mitochondrial disease – its impact, etiology, and pathology. Current Topics in Developmental Biology 77: 113–155.

Merlet J, Rubio‐Pena K, Al Rawi S and Galy V (2019) Autophagosomal sperm organelle clearance and mtDNA inheritance in C. elegans. Advances in Anatomy, Embryology, and Cell Biology (231): 1–24.

Meusel MS and Moritz RF (1993) Transfer of paternal mitochondrial DNAduring fertilization of honeybee (Apis mellifera L.) eggs. Current Genetics 24: 539–543.

Milani L, Ghiselli F, Guerra D, Breton S and Passamonti M (2013) A comparative analysis of mitochondrial ORFans: new clues on their origin and role in species with doubly uniparenta inheritance of mitochondria. Genome Biology and Evolution 5: 1408–1434.

Mossman JA, Slate J, Birkhead TR, Moore HD and Pacey AA (2012) Mitochondrial haplotype does not influence sperm motility in a UK population of men. Human Reproduction 27: 641–651.

Moyes CD, Battersby BJ and Leary SC (1998) Regulation of muscle mitochondrial design. Journal of Experimental Biology 201: 299–307.

Nishimura Y, Yoshinari T, Naruse K, et al. (2006) Active digestion of sperm mitochondrial DNA in single living sperm revealed by optical tweezers. Proceedings of the National Academy of Sciences of the USA 103: 1382–1387.

Oakes CC, La Salle S, Smiraglia DJ, Robaire B and Trasler JM (2007) Developmental acquisition of genome‐wide DNA methylation occurs prior to meiosis in male germ cells. Developmental Biology 307: 368–379.

Otani H, Tanaka O, Kasai K and Yoshioka T (1988) Development of mitochondrial helical sheath in the middle piece of the mouse spermatid tail: regular dispositions and synchronized changes. Anatomical Record 222: 26–33.

Peng L, Wen M, Liu Q, et al. (2018) Persistence and transcription of paternal mtDNA dependent on the delivery strategy rather than mitochondria source in fish embryos. Cellular Physiology and Biochemistry 47 (5): 1898–1908.

Politi Y, Gal L, Kalifa Y, et al. (2014) Paternal mitochondrial destruction after fertilization is mediated by a common endocytic and autophagic pathway in Drosophila. Developmental Cell 29 (3): 305–320.

Pollack Y, Kasir J, Shemer R, Metzger S and Szyf M (1984) Methylation pattern of mouse mitochondrial DNA. Nucleic Acids Research 12: 4811–4824.

Publicover SJ, Giojalas LC, Teves ME, et al. (2008) Ca2+ signalling in the control of motility and guidance in mammalian sperm. Frontiers in Bioscience 13: 5623–5637.

Reynier P, Chretien MF, Penisson‐Besnier I, et al. (1997) Male infertility associated with multiple mitochondrial DNA rearrangements. Comptes Rendus de l'Acade'mie des Sciences – Series III 320: 629–636.

Rojansky R, Cha MY and Chan DC (2016) Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. eLife 5.

Ruiz‐Pesini E, Lapena AC, Diez‐Sanchez C, et al. (2000) Human mtDNA haplogroups associated with high or reduced spermatozoa motility. American Journal of Human Genetics 67: 682–696.

Sano N, Obata M and Komaru A (2010) Mitochondrial DNA transmitted from sperm in the blue mussel Mytilus galloprovincialis showing doubly uniparental inheritance of mitochondria, quantified by real‐time PCR. Zoological Science 27: 611–614.

Sato M and Sato K (2011) Degradation of paternal mitochondria by fertilization‐triggered autophagy in C. elegans embryos. Science 334: 1141–1144.

Schwartz M and Vissing J (2002) Paternal inheritance of mitochondrial DNA. New England Journal of Medicine 347: 576–580.

Shimada K, Crother TR, Karlin J, et al. (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36: 401–414.

Shock LS, Thakkar PV, Peterson EJ, Moran RG and Taylor SM (2011) DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proceedings of the National Academy of Sciences of the USA 108: 3630–3635.

Shoubridge EA and Wai T (2007) Mitochondrial DNA and the mammalian oocyte. Current Topics in Developmental Biology 77: 87–111.

Song WH, Yi YJ, Sutovsky M, Meyers S and Sutovsky P (2016) Autophagy and ubiquitin‐proteasome system contribute to sperm mitophagy after mammalian fertilization. Proceedings of the National Academy of Sciences of the United States of America 113 (36): E5261–E5270.

de Sousa Lopes SM and Roelen BA (2010) An overview on the diversity of cellular organelles during the germ cell cycle. Histology and Histopathology 25: 267–276.

Spiropoulos J, Turnbull DM and Chinnery PF (2002) Can mitochondrial DNA mutations cause sperm dysfunction? Molecular Human Reproduction 8: 719–721.

Srirattana K and St John JC (2019) Transmission of dysfunctional mitochondrial DNA and its implications for mammalian reproduction. Advances in Anatomy, Embryology, and Cell Biology 231: 75–104.

St John J, Sakkas D, Dimitriadi K, et al. (2000) Failure of elimination of paternal mitochondrial DNA in abnormal embryos. Lancet 355: 200.

St John JC, Jokhi RP and Barratt CL (2001) Men with oligoasthenoteratozoospermia harbour higher numbers of multiple mitochondrial DNA deletions in their spermatozoa, but individual deletions are not indicative of overall aetiology. Molecular Human Reproduction 7: 103–111.

St John JC and Schatten G (2004) Paternal mitochondrial DNA transmission during nonhuman primate nuclear transfer. Genetics 167: 897–905.

St John JC, Jokhi RP and Barratt CL (2005) The impact of mitochondrial genetics on male infertility. International Journal of Andrology 28: 65–73.

St John JC, Facucho‐Oliveira J, Jiang Y, Kelly R and Salah R (2010) Mitochondrial DNA transmission, replication and inheritance: a journey from the gamete through the embryo and into offspring and embryonic stem cells. Human Reproduction Update 16: 488–509.

St John JC (2012) Transmission, inheritance and replication of mitochondrial DNA in mammals: implications for reproductive processes and infertility. Cell and Tissue Research 349: 795–808.

St John JC (2013) Mito Chondrial DNA, Mito Chondrial, Disease and Stem Cells (Stem Cell Biology and Regenerative Medicine 2013). Springer Science+Business Media: New York.

Storey BT (1980) Strategy of oxidative metabolism in bull spermatozoa. Journal of Experimental Zoology 212: 61–67.

Sutovsky P, Moreno RD, Ramalho‐Santos J, et al. (1999) Ubiquitin tag for sperm mitochondria. Nature 402: 371–372.

Sutovsky P, McCauley TC, Sutovsky M and Day BN (2003) Early degradation of paternal mitochondria in domestic pig (Sus scrofa) is prevented by selective proteasomal inhibitors lactacystin and MG132. Biology of Reproduction 68 (5): 1793–1800.

Sutovsky P and Song WH (2017) Post‐fertilisation sperm mitophagy: the tale of Mitochondrial Eve and Steve. Reproduction, Fertility, and Development 30 (1): 56–63.

Thompson WE, Ramalho‐Santos J and Sutovsky P (2003) Ubiquitination of prohibitin in mammalian sperm mitochondria: possible roles in the regulation of mitochondrial inheritance and sperm quality control. Biology of Reproduction 69 (1): 254–260.

Trounce I (2000) Genetic control of oxidative phosphorylation and experimental models of defects. Human Reproduction 15 (suppl. 2): 18–27.

Ursing BM and Arnason U (1998) The complete mitochondrial DNA sequence of the pig (Sus scrofa). Journal of Molecular Evolution 47: 302–306.

Wei Y, Chiang WC, Sumpter R Jr, Mishra P and Levine B (2017) Prohibitin 2 Is an Inner mitochondrial membrane mitophagy Receptor. Cell 168 (1–2): 224–238 e210.

Wolff JN, Sutovsky P and Ballard JW (2013) Mitochondrial DNA content of mature spermatozoa and oocytes in the genetic model Drosophila. Cell and Tissue Research 353: 195–200.

Yang Z and Klionsky DJ (2010) Mammalian autophagy: core molecular machinery and signaling regulation. Current Opinion in Cell Biology 22: 124–131.

Zhang J (2013) Autophagy and mitophagy in cellular damage control. Redox Biology 1: 19–23.

Zhao X, Li N and al GW (2004) Further evidence for paternal inheritance of mitochondrial DNA in the sheep (Ovis aries). Heredity 93: 399–403.

Zouros E, Freeman KR, Ball AO and Pogson GH (1992) Direct evidence for extensive paternal mitochondrial DNA inheritance in the marine mussel Mytilus. Nature 359: 412–414.

Zouros E and Rodakis GC (2019) Doubly Uniparental Inheritance of mtDNA: an unappreciated defiance of a general rule. Advances in Anatomy, Embryology, and Cell Biology 231: 25–50.

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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. http://www.els.net [doi: 10.1002/9780470015902.a0006165.pub3]