New patterns of inheritance in mitochondrial disease

doi:10.1016/j.bbrc.2003.09.037

Biochemical and Biophysical Research Communications

Volume 310, Issue 2, 17 October 2003, Pages 247-251

https://doi.org/10.1016/j.bbrc.2003.09.037 Get rights and content

Abstract

With the identification of a patient with mutated mitochondrial DNA (mtDNA) of paternal origin, it has been unequivocally proven that not only does paternal mtDNA survive in the zygote, but it can also contribute substantially to the mtDNA pool of adult, human skeletal muscle. The questions are: how often does paternal mtDNA inheritance occur and what mechanisms are involved? In this paper, we will review current knowledge on the fate of sperm mitochondria after fertilization and discuss the impact paternal inheritance may have on our understanding of mitochondrial biology.

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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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).
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Breakthroughs and ViewsNew patterns of inheritance in mitochondrial disease

Abstract

Section snippets

Dilution of paternal mtDNA in the embryo

Specific destruction of sperm mitochondria

Ubiquitination

In vitro fertilization

Recombination

Paternal inheritance does exist!

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Lancet

Am. J. Hum. Genet.

Trends Genet.

J. Biol. Chem.

Mol. Cell. Probes

Sequence and organisation of the human mitochondrial genome

Nature

Oxidative stress and mitochondrial DNA mutations in human aging

Proc. Soc. Exp. Biol. Med.

Uniparental inheritance of mitochondrial and chloroplast genes: mechanism and evolution

Proc. Natl. Acad. Sci. USA

The inheritance of genes in mitochondria and chloroplasts: laws, mechanisms, and models

Annu. Rev. Genet.

Maternal inheritance of human mitochondrial DNA

Proc. Natl. Acad. Sci. USA

Mitochondrial encephalopathies

Mitochondrial DNA and human evolution

Nature

Mitochondrial mutation rate revisited: hot spots and polymorphisms

Nat. Genet.

Mitochondrial genome variation and the origin of modern humans

Nature

Misconceptions about mitochondria and mammalian fertilization: implications for theories on human evolution

Proc. Natl. Acad. Sci. USA

Mitochondrial Steve: paternal inheritance of mitochondria in humans

Trends Ecol. Evol.

Mitochondrial DNA content of human spermatozoa

Biol. Reprod.

Mitochondrial DNA in mammalian reproduction

Rev. Reprod.

Mitochondrial DNA content affects the fertilizability of human oocytes

Mol. Hum. Reprod.

Paternal inheritance of mitochondrial DNA in mice

Nature

Is organelle DNA strictly maternally inherited? Power analysis of a binomial distribution

Am. J. Bot.

Breakthroughs and Views
New patterns of inheritance in mitochondrial disease