Abstract
It is textbook knowledge that the small multicopy mitochondrial genome (mtDNA) is maternally inherited in humans and mammals [1,2]. The uniparental mtDNA inheritance applies to most eukaryotic organisms, including animals exhibiting the doubly uniparental inheritance, such as the bivalve mollusks [3,4]. Occurrence of paternal mtDNA transmission has also been documented [5–7], and doubts on strict maternal inheritance in humans have been raised [8,9]. The best-documented case of paternal mtDNA inheritance was in a patient carrying a pathogenic mtDNA mutation [9], never replicated in following studies of patients with mitochondrial diseases due to various mtDNA defects [10–12]. The sperm mitochondria enter the oocyte during fertilization in mammals [13], but paternal mitochondria and mtDNA disappear at the initial cell divisions of the embryo in a stringently species-specific fashion [14]. In fact, the failure to efficiently eliminate paternal mtDNA from different species intercrosses [14,15] explains some of the cases of paternally inherited mtDNA [5]. Furthermore, recognition and targeted elimination of exogenous mtDNA entering the oocyte seems restricted to sperm mtDNA, not occurring with liver mtDNA, thus also displaying tissue specificity [16]. The way by which paternal mtDNA inheritance fails to occur in humans remains elusive, and it appears that several mechanisms have coevolved to avoid paternal mtDNA contribution to the embryo [17]. It has been observed that sperm mitochondria are ubiquitinated, suggestive of an “active elimination model” for paternal mtDNA [14], which may occur through different routes, such as proteosomal or lysosomal pathways [14,17]. Autophagy has been recently highlighted as the mechanism for paternal mtDNA elimination in Caenorhabditis elegans [18,19]. This was not observed in mice, for which elimination of mtDNA from prefertilization sperm and uneven persistence of paternal mtDNA in the embryo raised the possibility of a passive “dilution model” of disproportionate paternal versus maternal mtDNAs in mammals [20]. The consequent leakage of paternal mtDNA in the newborn may have remained “undetected” by the standard sequencing approaches.
Highlights
It has been observed that sperm mitochondria are ubiquitinated, suggestive of an “active elimination model” for paternal mtDNA [14], which may occur through different routes, such as proteosomal or lysosomal pathways [14,17]
Age and tissue-dependent preferential shifts of one mtDNA haplotype over the other have been documented in heteroplasmic mice carrying a mixture of BALB and NZB mitochondrial genomes [22], potentially applying to the greatly disproportionate paternal versus maternal mtDNA ratio in the newborn tissues according to the “dilution model.”
A non-random segregation of the mtDNA haplotypes occurs during tissue aging and germline transmission, leading to the proposal that this may explain the advantage of uniparental inheritance of mtDNA [23]
Summary
Occurrence of paternal mtDNA transmission has been documented [5,6,7], and doubts on strict maternal inheritance in humans have been raised [8,9]. The failure to efficiently eliminate paternal mtDNA from different species intercrosses [14,15] explains some of the cases of paternally inherited mtDNA [5].
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