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Mitochondria and Embryo Viability
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Irene Corachan Garcia, Laura Iñiguez Quiles, Antonio Diez-Juan
Human mtDNA is maternally inherited (24). Although a zygote receives both maternal and paternal mtDNA at fertilization, the paternal mtDNA is specifically targeted for degradation and removed from the cytoplasm of the zygote during embryogenesis (25,26). The number of mitochondria present in a metaphase II oocyte (19) represents only a small fraction of the maternal mtDNA pool due to a genetic bottleneck that occurs during oogenesis (27). In the primordial germ cells there is a large population of mtDNA that represents the maternal mtDNA pool. During germline development, this pool is subsampled to a relatively small number (24), resulting in only a small fraction of mtDNA being represented in the mature egg (27). This process limits mtDNA diversity in each oocyte and promotes homoplasmy. However, mtDNA differs across a cohort of oocytes because the maternal mtDNA is randomly segregated (27). Indeed, in mtDNA diseases, the level of mutant mtDNA differs between oocytes from the same patient (28). After the bottleneck, during oocyte maturation, both mitochondrial content and mtDNA copy number increase (27).
Patterns of Inheritance: Mendelian and Non-Mendelian
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Merlin G. Butler, Michael Begleiter, Shannon Lillis, Molly Lund, F. John Meaney
During cell division, the mitochondrial DNA replicates and sorts randomly among the new mitochondria, which are then randomly distributed among the new cells. Therefore, each of the new daughter cells would receive different proportions of mitochondria with normal or mutant mitochondrial DNA, if present. Homoplasmy is a term that refers to cells that contain a pure population of mitochondria and their DNA. Heteroplasmy refers to a state in which cells contain a mixture of mitochondria with mutant mtDNA and mitochondria with normal mtDNA. Varying proportions of mitochondria with mutations in their DNA may account for variability of symptoms and severity seen in mitochondrial genetic diseases even within the same family.
Mitochondrial Pathologies and Their Neuromuscular Manifestations
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Carlos Ortez, Andrés Nascimento
There are multiples copies of circular mtDNA in one mitochondrion, and some of these copies may carry nucleotide variants, i.e., base changes, not present in all mtDNA molecules (mtDNA polymorphisms or mtDNA mutations). Homoplasmy is characterized by the identity of all copies of the mitochondrial genome. Patients harbouring pathogenic mtDNA defects frequently have a mixture of mutated and wild-type mtDNA, and this is called heteroplasmy; the percentage of mutated mtDNA can vary among different organs within the same individual. Cells are able to tolerate high percentage levels of mutated mtDNA. Thus, the phenotypic expression of a pathogenic mtDNA mutation can be evident only if the number of mutant mtDNAs exceeds a certain threshold, which varies among tissues (30 to 80% of mutated mtDNA), depending upon their constitutive and acute requirements for OXPHOS2,7. Mutations in mtDNA that impair mitochondrial protein synthesis include mtDNA rearrangements (deletions or duplications), mutations in tRNA genes, and mutations in protein-coding genes2,7. Single deletions of mtDNA
Successful production of human epidermal growth factor in tobacco chloroplasts in a biologically active conformation
Published in Growth Factors, 2023
Yunpeng Wang, Jieying Fan, Niaz Ahmad, Wen Xin, Zhengyi Wei, Shaochen Xing
The homoplasmic plant lines were grown to maturity in a greenhouse under controlled environment conditions for progeny collection. The transplastomic plant lines displayed a normal phenotype compared with wt, despite of a bit growth delay at early stages, without any other observable drastic effects on plant fitness, e.g. dwarf (Castiglia et al. 2016). The lines were completely fertile and showed normal seed setting (Figure 1(D)). The seeds obtained from transplastomic and wt plants were grown on MS medium containing 500 mg L−1 spectinomycin to confirm: a) inheritance of the transgene(s) to the progeny, and b) to confirm the homoplasmy. Wt plants showed a complete bleaching in the presence of spectinomycin (Figure 3(A)) while the progenies of transplastomic plant lines were green and uniform, without showing any sign of bleaching (Figure 3(A)). Lack of any segregation event in the progenies confirmed the uniform inheritance of aadA cassette that was part of the construct as well as the homoplasmic status of the transplastomic plant lines.
Forensic evaluation of mitochondrial DNA heteroplasmy in Gujarat population, India
Published in Annals of Human Biology, 2022
Mohammed H. M. Alqaisi, Molina Madhulika Ekka, Bhargav C. Patel
The mitochondrial DNA is homoplasmic when all mitochondrial DNA molecules are identical. On the other hand, if mutant mtDNA coexists alongside wild-type mtDNA and has two distinct populations of mtDNA, it is called heteroplasmy (Melton 2004; Wallace and Chalkia 2013; Li et al. 2016). Heteroplasmy is primarily caused by the higher mutation rates observed in mitochondrial genomes compared to nuclear genomes (Brown et al. 1982; Wallace et al. 1987; Wallace and Chalkia 2013). Moreover, hypervariable regions are more susceptible to having heteroplasmies than other mitochondrial genome regions (Greenberg et al. 1983; Li et al. 2015). In mtDNA sequences, two forms of heteroplasmy may be found: point heteroplasmy (PH) and length/C-stretch heteroplasmy (LH). PH is the most common type of heteroplasmy used in forensic analysis. It is possible to detect two nucleotides as two peaks at a single position in an electropherogram, indicating the presence of PH (Figure 1). However, LH (Figure 2) is generally triggered when C residues are inserted or when thymine is substituted for cytosine (Bendall and Sykes 1995; Bendall et al. 1997; Lutz-Bonengel et al. 2008; Parson et al. 2014).
Maternal spindle transfer for mitochondrial disease: lessons to be learnt before extending the method to other conditions?
Published in Human Fertility, 2022
Charalampos Siristatidis, Themis Mantzavinos, Nikos Vlahos
Mitochondrial diseases (mtDNA diseases) are a group of serious conditions often affecting high energy requiring tissues, such as brain, muscle, liver, heart, and the Central Nervous System. They are clinically heterogeneous and may present with a variety of symptoms, such as dementia, deafness, diabetes, stroke, blindness, heart, kidney, and liver failure (Genetic Disease Foundation, 2010; Palacios-González, 2017). They are caused by either mutations in mitochondrial or nuclear genes, directly encoding structural or functional components of the mitochondrion. Reduction in the number of mtDNA copies can also be seen in affected tissues. mtDNA mutations are inherited through a maternal pattern. Affected individuals are ‘heteroplasmic’, carrying a mixture of normal and mutant mitochondria, the levels of which can differ among tissues, while genotype‐phenotype associations usually vary even within families (Gropman, 2001). In contrast, homoplasmic mutations occur in some of the thousands of copies of mtDNA within the same tissue or cell, e.g. oocytes, affecting all mtDNA copies, so that the same mtDNA variant exists in all copies (Marchington, 1998).