Biochemical and Biophysical Research Communications
Breakthroughs and ViewsNew patterns of inheritance in mitochondrial disease
Section snippets
Dilution of paternal mtDNA in the embryo
The sperm contributes to the fertilized oocyte’s pool of mitochondria (see Fig. 1). During fertilization, the mitochondria-rich mid-piece of the sperm tail also enters the egg. The number of mtDNA molecules within single spermatozoa is much lower than the mtDNA copies in the oocyte. It has generally been believed that the number of mtDNA copies in each spermatozoon is in the range of 50–100 [11], [12]. However, the number varies considerably in the literature, probably due to different methods
Specific destruction of sperm mitochondria
The finding by Gyllensten and co-workers of paternal mtDNA in mouse offspring has been questioned. Kaneda et al. [18] developed an assay capable of detecting sperm mtDNA in a single mouse embryo. They showed that in intraspecific hybrids of M. musculus, the paternal mtDNA disappeared after the pronucleus stage. In contrast, in interspecific hybrids between M. musculus and M. spretus, paternal mtDNA was detectable from the pronucleus stage to the newborn mouse. In the interspecific hybrids, the
Ubiquitination
One of the factors believed to be involved in the destruction and elimination of sperm mitochondria is the ubiquitination of sperm mitochondria. Ubiquitination is one of the processes in which a protein is tagged for further breakdown through proteolysis. This is achieved by covalent binding of the protein ubiquitin to the ε-amino group of the substrate’s lysine residues [21]. In several reports by Sutovsky and co-workers it has been documented that sperm mitochondria are tagged with ubiquitin
In vitro fertilization
Intracytoplasmic sperm injection (ICSI) is widely used in assisting reproduction. With this technique, a single spermatozoon is injected into the oocyte. To study the fate of the sperm mtDNA in humans, Danan et al. [26] investigated the mtDNA in 27 neonates born after ICSI. The techniques used allowed paternal mtDNA to be detected with a sensitivity level between 0.01% and 2%, using the highly polymorphic D-loop as a target for distinguishing paternal from maternal mtDNA. Following this
Recombination
Recombination of mtDNA is a phenomenon that has been heavily disputed over the years [28], [29], [30], [31], [32], [33], [34]. Recombination would imply either mitochondrial fusion or uptake of leaked and released paternal mtDNA into maternal mitochondria, and the existence of enzymes allowing recombination. The existence of homologous DNA recombination activity in mitochondrial extracts is documented, although it may only serve as part of an mtDNA repair system [35], [36], [37]. Fusion of
Paternal inheritance does exist!
With the identification of a patient in whom mutated mtDNA in muscle was of paternal origin, it has been proven that it is possible for paternally derived mtDNA to contribute substantially (90%) to the mtDNA pool of adult human skeletal muscle [39]. The paternal mtDNA in the patient harbored a 2-bp deletion in the ND2 gene, thus introducing a frame-shift and a premature stop codon close to the mutation. As a result, complex I activity was decreased below 5% of normal in the patient’s muscle.
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Cited by (45)
Genetics
2018, Principles and Applications of Molecular DiagnosticsExperimental strategies towards increasing intracellular mitochondrial activity in oocytes: A systematic review
2016, MitochondrionCitation Excerpt :The mtDNA copy number in unfertilized human oocytes have been quantified by competitive polymerase chain reaction (PCR) (Mootha et al. 2003), real time PCR (Kristián et al. 2006) and measuring the expression levels of mtDNA. mtDNA and mtDNA-nDNA interactions may lead to the different phenotypes resulting from nuclear cloning (Carling et al. 2011; Hsieh et al. 2002; Reynier et al. 2001; Schwartz and Vissing, 2002, 2003; Sutovsky 2004; Sutovsky et al. 2003a; Sutovsky et al. 2003b; Sutovsky et al. 1999; Sutovsky et al., 2004; Wu et al. 2002). It has been shown that mito-nuclear incompatibility associate with some genetic diseases and may be critical especially in the case of great sequence differences between the mtDNAs of the donor and acceptor that originate from different ethnicities (Gershoni et al. 2014).
Evolutionary perspectives on the links between mitochondrial genotype and disease phenotype
2014, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :Ultimately, the general relevance of the Sharpley et al. [159] study to our understanding of mitochondrial disease might hinge on the prevalence by which paternal mtDNA bypasses the process of ubiquitination [162] and becomes paternally inherited. Several such cases have now been reported in humans [163–166]. This review has highlighted the extraordinary genetic complexity that underpins the expression of mitochondrial disease.
Transmission of human mitochondrial DNA along the paternal lineage in transmitochondrial mice
2013, MitochondrionCitation Excerpt :Our present data raise the question whether such a protection exists and, if yes, how efficient it is. Analyzing the finding by Schwartz and Vissing (2003) of patient with paternally inherited mtDNA in the skeletal muscles, Williams (2002) proposed that there is no strict selection against distinct mtDNA in the cells of early embryos because the metabolic needs of an embryo are met primarily by glycolysis. Previous studies of healthy humans gave no evidence of paternal inheritance, but the samples studied may have been too small to allow detecting transmission of low amounts of paternal mtDNA.
Mitochondrial Disease
2012, Anesthesia and Uncommon Diseases: Sixth EditionBeyond the serotonin hypothesis: Mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders
2011, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :A maternal inheritance pattern has been established for some mtDNA mutations, including most point mutations and duplications. Paternal inheritance of mtDNA in a human has been reported only once (Schwartz and Vissing, 2003). The concept “Mitochondrial Medicine” was coined in 1994 by Rolf Luft who in 1962 reported the first case of a mitochondrial disorder in a female patient investigated at Karolinska Hospital in Stockholm (Luft, 1994; Luft et al., 1962).