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)