The domestic pig as a model for the study of mitochondrial inheritance
Maternal mitochondrial inheritance is a fundamental paradigm within reproductive biology, yet the molecular mechanisms which underlie this process remain poorly understood. The ubiquitin proteasome system (UPS) and branches of the autophagic pathway have been implicated in taking part in the active degradation of sperm mitochondria post-fertilization. Despite this knowledge, there remains much unknown about this process, including the cofactors and substrates involved, as well as the implications of what occurs when these systems of degradation fail. Mitochondrial inheritance research has utilized a variety of animal models. However, one model that is of particular importance, especially when attempting to link mitochondrial inheritance research to humans, is the domestic pig. Pigs offer relatively easy collection of gametes which are similar to those of humans. Furthermore, pigs are physiologically and anatomically more similar to humans than the majority of other model systems available. Porcine in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and novel cell-free systems are research tools which can be exploited to provide greater insight into the processes behind sperm mitochondrial degradation. In the future studies of mitochondrial inheritance, pigs will likely play a crucial role as an animal model system.
KeywordsMitochondria mtDNA Inheritance Ubiquitin Autophagy Proteasome Sperm Oocyte Fertilization
We thank Professor Rodney Geisert (MU Animal Science) for the image of the porcine female reproductive tract incorporated in Figure 1, and Professor Kathy Timms (MU OBGYN & Women’s Health) for permission to use unpublished data from a joint research project (Figure 2B). We appreciate our colleagues and collaborators, past and present who have been supporting our research on sperm mitophagy. Porcine gametes for our work have been provided reliably by the NIH National Swine Resource and Research Center (NSRRC), University of Missouri.
Work in our laboratory, directly pertinent to this manuscript has been funded by Agriculture and Food Research Initiative Competitive Grant no. 2013-67015-20961. Other research in our laboratory relevant to this review has been funded by the National Institute of Food and Agriculture (NIFA), U.S. Department of Agriculture (USDA) grant number 2015-67015-23231, grant number 5 R01 HD084353-02 from NIH National Institute of Child and Human Development, and seed funding from the Food for the twenty-first Century Program of the University of Missouri.
Compliance with ethical statements
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with animals performed by any of the authors.
- Aw WC, Garvin MR, Ballard JWO (2019) Exogenous factors may differentially influence the selective costs of mtDNA mutations. Adv Anat Embryol Cell BiolGoogle Scholar
- Galen (1586). Galeni Librorum Quarta Classis Apud luntas, Venetijs [Venice] Google Scholar
- Giuffra E, Kijas JM, Amarger V, Carlborg O, Jeon JT, Andersson L (2000) The origin of the domestic pig: independent domestication and subsequent introgression. Genetics 154:1785–1791Google Scholar
- Katayama M, Rieke A, Cantley T, Murphy C, Dowell L, Sutovsky P, Day BN (2007) Improved fertilization and embryo development resulting in birth of live piglets after intracytoplasmic sperm injection and in vitro culture in a cysteine-supplemented medium. Theriogenology 67:835–847CrossRefGoogle Scholar
- Kramer P, Bressan P (2019) Mitochondria inspire a lifestyle. Adv Anat Embryol Cell Biol 231Google Scholar
- Kuzmuk KN, Shook LB (2011) Pigs as a model for biomedical sciences. The Genetics of the Pig:426–444Google Scholar
- Losano JDA, Padin JF, Mendez-Lopez I, Angrimani DSR, Garcia AG, Barnabe VH, Nichi M (2017) The stimulated glycolytic pathway is able to maintain ATP levels and kinetic patterns of bovine epididymal sperm subjected to mitochondrial uncoupling. Oxidative Med Cell Longev 2017:1682393CrossRefGoogle Scholar
- Maddox-Hyttel P, Dinnyes A, Laurincik J, Rath D, Niemann H, Rosenkranz C, Wilmut I (2001) Gene expression during pre- and peri-implantation embryonic development in pigs. Reprod Suppl 58:175–189Google Scholar
- Mao J, O’Gorman C, Sutovsky M, Zigo M, Wells KD, Sutovsky P (2018) Ubiquitin A-52 residue ribosomal protein fusion product 1 (Uba52) is essential for preimplantation embryo development. Biol Open 7Google Scholar
- Merlet J, Rubio-Pena K, Al Rawi S, and Galy V (2019) Autophagosomal sperm organelle clearance and mtDNA inheritance in C. elegans. Adv Anat Embryol Cell Biol, 1–24Google Scholar
- Okamura N, Tajima Y, Soejima A, Masuda H, Sugita Y (1985) Sodium bicarbonate in seminal plasma stimulates the motility of mammalian spermatozoa through direct activation of adenylate cyclase. J Biol Chem 260:9699–9705Google Scholar
- Renner S, Fehlings C, Herbach N, Hofmann A, von Waldthausen DC, Kessler B, Ulrichs K, Chodnevskaja I, Moskalenko V, Amselgruber W et al (2010) Glucose intolerance and reduced proliferation of pancreatic beta-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function. Diabetes 59:1228–1238CrossRefGoogle Scholar
- Rogers CS, Hao Y, Rokhlina T, Samuel M, Stoltz DA, Li Y, Petroff E, Vermeer DW, Kabel AC, Yan Z et al (2008) Production of CFTR-null and CFTR-DeltaF508 heterozygous pigs by adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer. J Clin Invest 118:1571–1577CrossRefGoogle Scholar
- Rojansky R, Cha MY, Chan DC (2016) Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. Elife 5Google Scholar
- Shitara H, Kaneda H, Sato A, Inoue K, Ogura A, Yonekawa H, Hayashi JI (2000) Selective and continuous elimination of mitochondria microinjected into mouse eggs from spermatids, but not from liver cells, occurs throughout embryogenesis. Genetics 156:1277–1284Google Scholar
- Song WH, Sutovsky P (2018) Porcine cell-free system to study mammalian sperm mitophagy. Methods Mol BiolGoogle Scholar
- Sutovsky P (2018) Pig overview (male reproduction). In: B Jegou B, skinner MK (eds), Encyclopedia of reproduction second edition vol. 1 Google Scholar
- Sutovsky P, Hewitson L, Simerly CR, Tengowski MW, Navara CS, Haavisto A, Schatten G (1996a) Intracytoplasmic sperm injection for Rhesus monkey fertilization results in unusual chromatin, cytoskeletal, and membrane events, but eventually leads to pronuclear development and sperm aster assembly. Hum Reprod 11:1703–1712CrossRefGoogle Scholar
- Wei Y, Chiang WC, Sumpter R Jr, Mishra P, Levine B (2017) Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell 168(224–238):e210Google Scholar
- Yen, N.T., Lin, C.S., Ju, C.C., Wang, S.C., and Huang, M.C. (2007). Mitochondrial DNA polymorphism and determination of effects on reproductive trait in pigs. Reproduction in domestic animals = Zuchthygiene 42, 387-392Google Scholar