Dynamic regulation of mitochondrial genome maintenance in germ cells

Reproductive Medicine and Biology, Aug 2013

Mitochondria play a crucial role in the development and function of germ cells. Mitochondria contain a maternally inherited genome that should be transmitted to offspring without reactive oxygen species-induced damage during germ line development. Germ cells are also involved in the mitochondrial DNA (mtDNA) bottleneck; thus, the appropriate regulation of mtDNA in these cells is very important for this characteristic transmission. In this review, we focused on unique regulation of the mitochondrial genome in animal germ cells; paternal elimination and the mtDNA bottleneck in females. We also summarized the mitochondrial nucleoid factors involved in various mtDNA regulation pathways. Among them, mitochondrial transcription factor A (TFAM), which has pleiotropic and essential roles in mtDNA maintenance, appears to have putative roles in germ cell regulation.

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Dynamic regulation of mitochondrial genome maintenance in germ cells

Katsumi Kasashima 0 1 Yasumitsu Nagao 0 1 Hitoshi Endo 0 1 0 Y. Nagao Center for Experimental Medicine, Jichi Medical University , Shimotsuke, Tochigi 329-0498, Japan 1 K. Kasashima H. Endo (&) Department of Biochemistry, Jichi Medical University , 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan Mitochondria play a crucial role in the development and function of germ cells. Mitochondria contain a maternally inherited genome that should be transmitted to offspring without reactive oxygen species-induced damage during germ line development. Germ cells are also involved in the mitochondrial DNA (mtDNA) bottleneck; thus, the appropriate regulation of mtDNA in these cells is very important for this characteristic transmission. In this review, we focused on unique regulation of the mitochondrial genome in animal germ cells; paternal elimination and the mtDNA bottleneck in females. We also summarized the mitochondrial nucleoid factors involved in various mtDNA regulation pathways. Among them, mitochondrial transcription factor A (TFAM), which has pleiotropic and essential roles in mtDNA maintenance, appears to have putative roles in germ cell regulation. - The mitochondrion, which is referred to as the cellular power plant, is an intracellular organelle that produces the majority of cellular ATP through oxidative phosphorylation. Besides this function, mitochondria are also important for the induction of apoptosis, and generate reactive oxygen species (ROS) by respiration. Mitochondria contain their own genomic DNA called mitochondrial DNA (mtDNA) [1]. In animals, mtDNA exists in multiple copies per cell ([1000 copies), and is maternally inherited from egg cells [2]. Human mtDNA is a 16.6 kb circular doublestranded DNA that encodes 13 proteins, which are components of respiratory chain subunits. mtDNA-encoded proteins are translated through mitochondrial ribosomes, and their expression is essential for respiratory function. Germ cells are essential for the generation of offspring and need to be protected from the accumulation of damaged mtDNA due to ROS. Respiration activity was shown to be suppressed in Xenopus oocytes and the resultant reduced levels of ROS have been suggested to enable accurate mtDNA transmission between generations [3]. It has recently been clarified that mitochondrial genomes and their products (including ribosomal RNA) play important roles in the formation and development of germ cells [47], which makes the mitochondrial genome the target for reproductive technology. Mitochondrial transfer (mtDNA replacement) has been attempted as a germline gene therapy for mitochondrial diseases [8] and the efficient development of aged oocytes [9]. However, mitochondrial transfer by replacing the cytoplasm may cause mtDNA carryover and heteroplasmy, in which two or more mtDNA variants co-exist. Since mouse mtDNA heteroplasmy causes reduced physical activity and learning [10], regulating mtDNA segregation, uniparental transmission, and the bottleneck seems to be important for maintaining its homoplasmy. In this review, we summarized characteristic regulation of the mitochondrial genome in germ cells, such as maternal inheritance and the mtDNA bottleneck (Fig. 1). In addition, we reviewed current understanding of the Fig. 1 Characteristic mtDNA regulation in germ cells. Schematic representation of mtDNA regulation in germ cells, maternal inheritance, and the mtDNA bottleneck. In females, the rapid segregation of mtDNA is enabled by the mtDNA bottleneck during PGCs and mature oocytes. There are three possible mechanisms in the mtDNA bottleneck, all of which are based on the low segregation unit number. In males, a decrease in mitochondria occurs during spermatogenesis, which includes a reduction in the mtDNA copy number and trimming of mitochondria. After fertilization, selective degradation of paternal mitochondria by autophagy or proteasomes further enhances the maternal inheritance of mtDNA major mitochondrial nucleoid factor TFAM, which has pleiotropic functions and may regulate the mtDNA copy number in germ cells. Maternal inheritance of the mitochondrial genome In most organisms, mtDNA is maternally inherited and transmitted to offspring, although paternal mitochondria enter into the egg cell after fertilization [11]. Maternal inheritance has been explained by differences in the size of the gamete; the paternal gamete (sperm) is much smaller than the maternal gamete (egg). The mtDNA copy number in germ cells is also very different; in animals, the egg cell contains 1058 copies of mtDNA [2], whereas mature sperm contain only 100 [12, 13]. A dilution of sperm mtDNA in the ooplasm has been considered as a simple model for explaining maternal inheritance. However, chloroplast DNA is inherited from the maternal gamete in Chlamydomonas reinhardtii, in which the size of the two gametes is similar [14], and this is caused by the active digestion of paternal DNA [15]. Thus, some active eliminating (...truncated)


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Katsumi Kasashima, Yasumitsu Nagao, Hitoshi Endo. Dynamic regulation of mitochondrial genome maintenance in germ cells, Reproductive Medicine and Biology, 2014, pp. 11-20, Volume 13, Issue 1, DOI: 10.1007/s12522-013-0162-0