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The cell cycle, including the mitotic cycle and organelle division cycles, as
revealed by cytological observations
Article in Journal of electron microscopy · August 2011

DOI: 10.1093/jmicro/dfr034 · Source: PubMed
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Journal of Electron Microscopy 60(Supplement 1): S117–S136 (2011)
doi: 10.1093/jmicro/dfr034
........................................................................................................................................................................................................................................................
60th Anniversary Issue: Biological

The cell cycle, including the mitotic cycle and organelle
division cycles, as revealed by cytological observations
Yuuta Imoto, Yamato Yoshida, Fumi Yagisawa, Haruko Kuroiwa
and Tsuneyoshi Kuroiwa*
Research Information Center for Extremophiles, Graduate School of Sciences, Rikkyo University,
3-34-1 Nishiikebukuro, Toshimaku, Tokyo 171-0825, Japan
*To whom correspondence should be addressed. E-mail: [email protected], [email protected]
..............................................................................................................................................................................................
Abstract It is generally believed that the cell cycle consists essentially of the
mitotic cycle, which involves mitosis and cytokinesis. These processes
Downloaded from http://jmicro.oxfordjournals.org/ by guest on August 24, 2015

are becoming increasingly well understood at the molecular level.
However, successful cell reproduction requires duplication and segre-
gation (inheritance) of all of the cellular contents, including not only the
cell-nuclear genome but also intracellular organelles. Eukaryotic cells
contain at least three types of double membrane-bounded organelles (cell
nucleus, mitochondria and plastids), four types of single membrane-
bounded organelles (endoplasmic reticulum, Golgi apparatus, lysosomes
and microbodies) and the cytoskeleton, which comprises tubulin-based
structures (including microtubules, centrosome and spindle) and actin
microfilaments. These membrane-bounded organelles cannot be formed
de novo and daughter organelles must be inherited from parent organelles
during cell cycle. Regulation of organelle division and its coordination
with the progression of the cell cycle involves a sequence of events that
are subjected to precise spatio-temporal control. Considering that the
cells of higher animals and plants contain many organelles which tend to
behave somewhat randomly, there is little information concerning the div-
ision and inheritance of these double- and single-membrane-bounded
organelles during the cell cycle. Here, we summarize the current cytologi-
cal and morphological knowledge of the cell cycle, including the division
cycles of seven membrane-bounded and some non-membrane-bounded
organelles. The underlying mechanisms and the biological relevance of
these processes are discussed, particularly with respect to cells of the
primitive alga Cyanidioschyzon merolae that have a minimum of orga-
nelles. We discuss unsolved problems and future perspectives opened by
recent studies.
..............................................................................................................................................................................................
Keywords cell cycle, organelle-division cycle, mitochondrial-division cycle,
chloroplast-division cycle, microbody-division cycle, Golgi apparatus-div-
ision cycle
..............................................................................................................................................................................................
Received 17 January 2011, accepted 19 April 2011
..............................................................................................................................................................................................
Introduction of the cell cycle are generally understood to corre-

Cells reproduce by duplication of their contents spond to the mitotic cycle. Using autoradiography,
and subsequent division. This cycle of duplication Howard and Pelc [1] discovered that nuclear DNA is
and division is called the cell cycle, and the events synthesized during a stage of interphase designated
........................................................................................................................................................................................................................................................
© The Author 2011. Published by Oxford University Press [on behalf of Japanese Society of Microscopy]. All rights reserved.
For permissions, please e-mail: [email protected]
S118 J O U R N A L O F E L E C T R O N M I C R O S C O P Y , Vol. 60, Supplement 1, 2011
as S-phase. The S phase is followed by a gap (G2 cytological techniques. The plastid DNA synthesis
phase), nuclear and cell division (M phase) and a phase ( pt-S) during the cell cycle of cultured BY-2
second gap (G1 phase) before the next S phase. cells was examined by 3H-thymidine autoradiog-
The functions of these phases have been identified raphy following medium renewal. The timing of the
in many cells, including human and yeast cells [2,3]. pt-S phase differed from that of the mitotic S phase.
It is generally believed that the structural and func- These observations suggest that the PD cycle pro-
tional aspects of the cell cycle are primarily associ- ceeded independently from the mitotic cycle [7].
ated with the cell nucleus. However, the cell also Plastid and mitochondrial DNA syntheses were also
contains organelles enclosed by double membranes observed in root meristem and cultured BY-2 cells
(mitochondria and plastids) and by a single mem- by immunofluorescence microscopy of Technovit
brane (endoplasmic reticulum (ER), dictyosomes of sections using an antibody against 5-bromodeoxy
the Golgi apparatus and lysosomes or vacuoles). uridine (BrdU) and co-fluorescent staining with
Clearly, successful cell reproduction requires faith- DAPI and quantitative Southern hybridization [8]. It
ful duplication and segregation of all of the cellular was shown that large quantities of both mitochon-
contents, which includes the intracellular organelles drial and plastid DNA were preferentially syn-

as well as the nuclear genome. Mitochondria and thesized prior to S-phase. However, in plants,
plastids are regarded as descendants of endosym- animals and fungi, it has been difficult to determine
biotic prokaryotes. They have their own DNA and the timing of each phase of the division cycle of
proliferate by division. Regulation of organelle div- double-membrane-bounded organelles. However,
ision and its coordination with the progression of the difference in the timing of the organelle S-phase
the cell cycle involves a sequence of events that are and mitotic S-phase has been established.
subjected to a precise spatio-temporal control. To Partitioning or division (inheritance) of single-
understand the cell cycle, we need to recognize mem-brane-bounded organelles occurs in many
coordination between the mitotic cycle and orga- organisms. Additionally, the dynamics of cyto-
nelle division cycles. Therefore, it is important to skeletal proteins and of centrosomes, which play
survey the division cycle of double- and major roles in the cell transport system and in cell
single-membrane-bounded organelles and the division during the mitotic cycle, must be examined
dynamics of cytoskeleton during the cell cycle. during the cell cycle [2,3]. During G1 phase, the two
We have proposed the concept of the ‘mitochon-
drial division (MD) cycle’ analogous to the mitotic
cycle [4–6]. In the plasmodium of the slime mold
Physarum polycephalum, mitosis and the mitotic
cycle are naturally synchronized and, in addition,
the mitochondria contain large rod-shaped com-
plexes of DNA and proteins, termed nucleoids. The
mitotic and MD cycles were precisely examined
using 3H-thymidine autoradiography and it was
shown that mitochondrial phases of the division
cycle, i.e. mt-S, mt-G2, mt-M and mt-G1 lasted 7.7,
2, 1.5 and 3 h, respectively, while the mitotic S, G2
and M phases lasted 6, 7 and 1 h, respectively. G1
lasted for a very short time. Although the timing of
the phases of the mitotic and MD cycles differed
markedly, the total generation time of the mitotic
cycle (14 h) was the same as that of mitochondria
(Fig. 1). Fig. 1 Diagram of the mitotic cycle of P. polycephalum. The cycle
proceeds clockwise. The outer circle represents mitochondrial events
The plastid division (PD) cycle was examined in and the inner circle depicts cell nuclear events. The duration of each
tobacco Bright Yellow 2 (BY-2) cells using phase is shown in hours. This figure was adapted from Ref. [5].
Y. Imoto et al. Cell cycle and organelle division cycles S119
orthogonal centrosomes separate. In general, in organelles, and of non-membrane-bounded orga-

these multi-organelle organisms, it has been difficult nelles, during cell cycle could be inferred from the
to demonstrate each division or partitioning of images of the chloroplasts in living cells.
double-and single-membrane-bounded organelles Here, we review the current cytological and mor-
because the cells contain large numbers of these phological knowledge concerning the cell cycle,
organelles and divisions or partitioning occur more including the division cycles of seven
or less randomly (mitochondrial and plastid fusion membrane-bounded-organelles (cell nucleus,
may also occur). mitochondria, chloroplasts, microbodies, lysosomes,
The unicellular red alga Cyanidioschyzon the Golgi apparatus and ER) and non-memb-rane-
merolae is a very small organism (1.5–2.0 μm diam- bounded organelles (centrosomes and spindle). We
eter), whose cells offer unique advantages for discuss the underlying mechanisms and the biologi-
studies of double- and single-membrane-bounded cal relevance of this process, particularly in C.
organelle division cycles. They contain a minimal merolae cells in comparison with other organisms
set of organelles; i.e. a cell nucleus, a mitochon- (Fig. 2). Furthermore, we discuss unsolved funda-
drion, a chloroplast, a microbody, an outer nuclear mental problems of the cell cycle related to the

membrane/ER, a single Golgi apparatus and a few mitotic and organelle division cycles and future per-
lysosomes [9–11]. Its organelle divisions can be spectives opened up by recent studies.
highly synchronized with the light/dark cycle. The
genome of C. merolae has been completely Division cycle and inheritance of
sequenced and it is one of the smallest genomes double-membrane-bounded organelles
(16.5 Mb), with the lowest number of genes among (cell nuclei, mitochondria and plastids)
free-living eukaryotes [9,12]. Because most of the
genes are present in low copy numbers and lack Mitotic cycle
introns, they are suitable for identifying functioning The typical eukaryotic cell cycle is divided into G1,
genes by proteome and transcriptome analysis. S, G2 and M phases [2,3]. The generation times and
Moreover, microarray analysis of its gene the durations of each phase have been determined
expression profile during organelle division and in many organisms, for example, the generation
inheritance was recently reported [13]. time of the plant Crepis capillaries is 10.4 h, com-
Besides studies of the mitotic cycle, MD and PD prising the DNA synthesis phase (S phase 5.1 h),
cycles have been examined by genome analysis the gap between S phase and M phase (G2 phase
[9,12], matrix assisted laser desorption ionization 2.2 h), mitosis (M phase 1.5 h) and the gap between
time of flight mass spectrometry (MALDI-TOF-MS) M and S phases (G1 phase 1.6 h) [22,23]. The con-
[14–17] and gene targeting [15–19]. The myosin gene densed mitotic chromosomes are readily visible in
was absent from the genome [9,12] and actin genes almost all cells of Bikonta, Opisthokonta and
were not expressed. Therefore, microfilaments and Amoebozoa [2,3]. In the case of budding yeasts, the
intermediate filaments could not be identified 16 condensed meiotic chromosomes are readily
throughout cell cycle by transcriptome and pro- visible [24], but are less easily seen in mitosis [2,3].
teome analyses [9,13]. In addition, during G1 phase, The cytological mechanisms for condensation of
cytoskeletal microtubules are absent [20]. chromosomes from interphase to mitosis have been
Miyagishima et al. [21] presented time-lapse video examined in detail in plants using high-resolution
images of C. merolae during the M phase under electron microautoradiography [24–27] and the mol-
phase contrast light microscopy. The images were ecular mechanism of chromosome condensation in
taken at 20 min intervals for the first 220 min after animals have been summarized by Hirano [28]. The
the onset of the chloroplast division, and at 10 min cell divides by forming a partition and splitting in
intervals, starting 340 min after the onset of the two. Cytokinesis occurs by actin contractile rings
chloroplast division [21]. The temporal sequence of [2,3]. In contrast to the situation in higher eukary-
electron microscopic images of the division process otic cells, the nuclear envelop of the yeast cell does
of double- and single-membrane-bounded not break down during M phase. The microtubules
Fig. 2 Summary of the division cycles and the temporal relationships of the three double-membrane-bounded organelles (cell nucleus,
mitochondrion and chloroplast ( plastid)) and the four single-membrane-bounded organelles (ER, Golgi apparatus, lysosome and microbody)
and centrosome in Cyanidioschyzon merolae cells. Each C. merolae cell has a minimum set of organelles comprising one cell nucleus, one
mitochondrion and one chloroplast, simple ER, one Golgi apparatus, one microbody and a few lysosomes. The organelle divisions can be
highly synchronized by the light/dark cycle. Chloroplast, mitochondrion and cell nucleus divisions occur in that order. Mitotic chromosomes
are not organized at M phase. Chloroplast and mitochondrion divide using the chloroplast (PD ring) and MD machineries (MD ring),
respectively. Microbody and lysosome are inherited using the mitochondrion as a carrier. Tubulins are absent in G1 phase, synthesized as a
monomer in S and organized into mitochondrial spindle and mitotic spindles in M phase. Mitotic cycle: G1, S, G2, M; MD cycle:
mitochondrial G1 phase (mt-G1), mitochondrial S phase (mt-S), mitochondrial mitotic phase (mt-M); and plastid cell cycle: plastidG1 phase
(pt-G1), plastid S phase ( pt-S), plastid division phase ( pt-M), the division cycles of the ER, Golgi apparatus, lysosome, microbody, and the
non-membrane-bounded organelle (centrosome). Double arrowheads indicate the time point of the organelle replication and single
arrowheads indicate the time point of the organelle division. Time shows hours after the second cell cycle.
of the mitotic spindle form inside the nucleus and with DAPI. The results were consistent with the
are attached to the spindle pole bodies at its previous data. The pt-S phase of the PD cycle and
periphery. the mt-S phase of the MD cycle always preceded
Currently, it appears that the cell cycle is com- the S phase of the mitotic cycle by approximately
posed of a mitotic cycle, a MD cycle, a PD cycle, a 1 h. The division of the plastid was completed first,
microbody division cycle, a lysosome (vacuole) div- followed by the mitochondria, and then, finally, by
ision cycle, a Golgi apparatus division cycle and an the cell nuclei. The durations of each phase of the
ER division cycle. Organelle division in C. merolae MD (mt-G1, 12 h; mt-S 1 h; mt-G2, 4 h; mt-M, 2 h)
can be highly synchronized by a light/dark cycle and PD cycles ( pt-G1, 14 h; pt-S, 1 h; pt-G2, 2 h;
and, under those conditions, the divisions of Golgi pt-M, 2 h) could be estimated. These observations
apparatus, chloroplast, mitochondria, microbody, clearly demonstrated that the cell cycle should be
lysosomes, cell-nucleus, ER and finally cytokinesis understood not only in terms of the mitotic cycle,
occur in that order. Based on studies of slime but also in terms of MD and PD cycles.
molds and higher plants, it has been suggested that These data indicate that the cell cycle is com-
the cell cycle is composed of a mitotic cycle, a MD posed of mitotic, MD and PD cycles, which appear

cycle and a PD cycle. to proceed independently of each other. In
In 1994, Suzuki et al. [29] examined the coopera- C. merolae, chloroplasts, mitochondria and cell
tive behavior of double-membrane-bounded orga- nuclei divided in that order, while in the primitive
nelles (cell nuclei, mitochondria and plastids) red alga Cyanidium caldarium, the sequence was
during the cell cycle of C. merolae by epifluores- chloroplasts, cell nuclei and mitochondria [32,33].
cence microscopy and fluorometry after staining Therefore, there a mechanism that determines the
with DAPI, using a video-intensified microscope order of chloroplasts, cell nuclei and MDs must be
photon-counting system (VIMPCS). The mitochon- present. Moreover, in multi-organelle organisms
drial DNA and the chloroplast DNA were syn- such as Amoebozoa, Biokonta and Opithsokonta,
thesized during stage I (G1 phase), while the the mechanism that determines the order of orga-
cell-nuclear DNA was duplicated in stage II nelle divisions must be even more complex.
(S phase). The mitochondrial and chloroplast div- A feature of cell-nuclear behavior observed
isions began simultaneously in stage II, and chloro- during the G1 phase of C. merolae was that the
plast division finished just prior to MD. The lower end of the cell-nucleus protruded at the
mitochondrial and chloroplast-nuclear divisions center of the mitochondrion, which in turn became
were completed in stage IV (M phase). The gener- doughnut-shaped [20]. In this cell, the cell-nucleus
ation time of this cycle was 28 h. They were able to possessed a single central nucleolus and associated
identify the duration of each phase of the cell chromatins, which consisted of a set of three homo-
cycles (G1 phase, 19 h; S phase, 6 h; G2 phase, 2 h; geneous copies of the ribosomal gene and one
M phase, 1 h). On the basis of these data, Itoh et al. histone gene. At this stage, a cytoskeleton and cyto-
[30,31] suggested relationships between the mitotic skeletal proteins (actin, 10 nm filaments, tubulin)
cycle and chloroplast, mitochondrial, and micro- were absent in cells of C. merolae although cells at
body division cycles in C. merolae using electron G1 phase (10 h) moved actively as amoebae.
microscopy. However, they could not determine the Therefore, the dynamic changes exhibited by intra-
timing of each phase of MD and PD cycles. cellular organelles must have been performed
To determine the timing of each of the G1, S, G2 without a cytoskeleton. During the S phase, the
and M phases of the cell nuclear divisions, and of lower end of cell-nucleus was taken out so that the
the mitochondrial (mt-G1, mt-S, mt-G2 and mt-M) cell-nucleus containing the nucleolus became
and plastid ( pt-G1, pt-S, pt-G2 and pt-M) phases spherical. Tubulin molecules were synthesized as
during cell cycle, Imoto et al. [20] measured the monomers and they diffused throughout the entire
DNA content of each cell nucleus, mt-nucleus cytoplasm for about 1.5 h during the S phase.
(mt-nucleoid) and pt-nucleus ( pt-nucleoid) directly Probably, the single mother centrosome core
using an improved VIMPCS method, after staining (without microtubules) was formed in the
cytoplasm near the peripheral end of the mitochon- condensin family are present; (d) Cytokinesis
drion during early S phase and it was replicated occurs in the absence of a contractile rings of actin.
and divided into two daughter centrosome cores In preliminary experiments, EF1α has been located
during late S phase (unpublished data). For 1 h in the contractile ring region, and it is likely that
during the G2 phase, the cell nucleus became this protein controls cytokinesis in many eukaryotic
football-shaped. Microtubules were focused on two cells (Imoto Y, Nishida K, Yagisawa F, Yoshida M,
daughter centrosome cores and formed centro- Yoshida Y, Ohnuma M, Fujiwara T, Kuroiwa H and
somes. For 2 h during the early M phase, the Kuroiwa T. unpublished data) (Fig. 3b).
nucleus changed from a football-like structure into
a Napoleon hat-like configuration (inverted cup) of
which the two ends were associated with the cen- Mitochondrial behavior
trosomes. Several microtubules extended from the As described above, the concept of the organelle
centrosomes and were positioned on the mitochon- division cycle has been evoked by the MD cycle of
drion to form a mitochondrial spindle. The nucleo- P. polycephalum. Mitochondria have their own
lus began to move from the central region of the DNA which is organized using basic proteins to

cell nucleus to the upper region. For 2 h, during the form organelle nuclei (nucleoids). Organelle nuclei
middle M phase, the cell nucleus became peanut- are universal in eukaryotes and the mechanism of
shaped and homogenous. During metaphase, rod- condensation of mitochondrial nuclei has been
shaped mitotic chromosomes were never observed summarized [6,35,36]. Mitochondrial nuclei are syn-
although condensins (multi-subunit protein thesized during a specific phase of the MD cycle,
complex that play a central role in mitotic chromo- which consists of the mt-S phase, the mt-G2 phase,
some assembly and segregation) [28] were present the mt-M phase, and the mt-G1 phase. The mt-M
and a mitotic nuclear spindle was formed between phase is characterized by two main events: division
daughter centrosomes. Consequently, chromosome of the mitochondrial nuclei, which is followed by
condensation did not occur in C. merolae although division of the matrix (the so-called MD or mito-
CENH3-containing kinetochores reconstituted into chondriokinesis). The mechanism of mitochondrial
two separate dot and co-localized with centrosomes nuclear division has been summarized by Kuroiwa
during early metaphase and drew uncondensed et al. [35].
regions of the chromosomal arms into the daughter Mitochondriokinesis occurs after mitochondrial
cell nuclei [34] (Fig. 3a). For 2 h during late M nuclear division and in this respect it resembles bac-
phase, the dumbbell-shaped cell nucleus divided terial cytokinesis. We have described the fine struc-
into daughter cell nuclei by the activity of mitotic ture and dynamics of the MD ring which provide the
spindle. The central spindle then pushed the daugh- morphological bases for mitochondriokinesis
ter cell nuclei apart from the daughter cells. The [37,38]. Electron microscopic studies first identified
daughter nuclei then changed back from being cup- a small electron-dense ring at the constriction sites
shaped to spherical and cytokinesis occurred in the of dividing mitochondria in P. polycephalum and,
absence of an actin cytoskeleton [9,32]. After the subsequently, similar structures have been observed
mitotic division, the cell-nucleus with its central in Nitella flexilis [6], Nannochloropsis oculata [39]
nucleolus resumed a spherical shape, suggesting and higher plants [38]. However, in multi-organelle
that a part of cell nucleus did not protrude into organisms such as animal and plants, it was difficult
mitochondrion. to examine the timing of each phase of the MD cycle
Aspects of C. merolae cell division differ from and of the MD ring because their cells have many
that observed in other cells and are summarized as organelles which divide asynchronously, and the
follows: (a) Tubulin synthesis is confined to a single ring is too small to be studied.
phase, and tubulin and actin do not exist during G1 As C. merolae cell has a simple disc-shaped mito-
phase; (b) A mitochondrial spindle is present; (c) chondrion between a single cell nucleus and a
Condensation of chromosomes does not occur single chloroplast, it is easy to observe the behavior
during M phase although proteins from the of the mitochondrion throughout the cell cycle. The

Fig. 3 (a) Immunofluorescent micrographs showing the cell nucleus in C. merolae during G2 and M phase. (a–d) Phase contrast
immunofluorescence images of DAPI (blue), CENH3 (green) indicating centromere and α-tubulin (red) in M phase cell. DAPI-stained cell
nucleus (white arrowheads) shows that chromosome condensation did not occur in C. merolae. (e–h) Immunofluorescence images of CENH3
(green) and DAPI (blue) through cell cycle. Dispersed CENH3 signals are focused on centrioles at M phase. (i) Model of the M phase
(metaphase) cell of C. merolae. Scale bar, 2 μm. This figure includes photographs that appeared in Refs [20] (a–d) and [34] (e–h).
(b) Immunofluorescent micrographs showing the early cytokinesis in C. merolae. (a–d) Phase contrast immunofluorescence images of DAPI
(blue), EF1α (green) indicating and α-tubulin (red) in early cytokinesis cell. The signals of EF1α are detected in the contractile ring region
(white double arrow heads).
time course has been deduced from fluorescence machinery. The microbody then moved from the
images using the VIMPCS system [20], and from end to the central region of mitochondrion and
living cells [21]. The morphological changes of the attached to the outer ring of the MD machinery.
organelles were as follows. For 9 h during early and The centrosomes of the mitochondrial spindle were
middle mitotic G1 phase (mitochondrial G1 phase), formed at the each end of mitochondrion. For 2 h
the mitochondrion exhibited a discoidal shape, during prophase (late mt-G2), the microbody began
dented at the center because the cell nucleus pro- elongating along the MD machinery of the cup-
truded into the mitochondrion. During late G1 shaped mitochondrion and surrounded the outer
phase (mt-S phase), as the hollow center of the ring of the MD machinery. The MD machinery then
mitochondrion became flat again, the nucleus began to contract at the division site. Nishida et al.
became disc-shaped, and then quickly elongated. [40–43] examined the structure and function of the
The mitochondrion synthesized its own DNA for MD ring in detail. The MD machinery was com-
about 1.5 h. During S (early mt-G2) phase for 2 h, posed of the outer machinery (outer MD ring,
the mitochondrion extended into an elongated dynamin ring, Mda1 ring) and the inner machinery
disc-shaped structure and the microbody attached (inner MD ring, FtsZ ring). By the contraction of
to the peripheral end of mitochondrion. For 1 h MD machinery, the mother mitochondrion divided
during G2 phase (middle mt-M), the MD machinery, into two daughter mitochondria. For 2 h during
composed of an inner matrix ring and an outer metaphase (mt-M phase), the dumbbell-shaped
cytoplasmic ring, was formed at the division site, mother microbody divided and separated into
immediately after formation of plastid-dividing (PD) spherical daughter microbodies by the activities of
electron-dense patches (50 nm in diameter) at each to colocalize with FtsZ. ZED proteins are expressed
side of the microbody, and microtubules of the just before MD. ZED interacted with FtsZ1 to form
mitochondrial spindle. During anaphase (mt-M the basic structure of the MD machinery and was
phase), each microbody detached from the daugh- required for the MD. Bacterial ZapA and mitochon-
ter mitochondria and mitosis and cytokinesis then drial ZED were also functionally very similar, which
occurred [37,40–43]. Recent interesting progress in implies that the bacterial cell division system was
the field is that MD machineries have now been iso- incorporated into the MD machinery during evol-
lated from C. merolae cells [16]. A novel ZapA-like ution with subsequent loss of most of the bacterial
bacterial protein, ZED, has provided new insights dividing genes.
into MD and the birth of eukaryotic cells.
Bacterial cell division systems that include FtsZ
have been found throughout prokaryotes. Mitochon-
dria arose from an endosymbiotic α-proteobacterial Plastid (chloroplast)behavior
ancestor and proliferate by division. However, it was The division of plastids (chloroplasts) is universally
previously unclear how the MD system was estab- present in Biokonta. As mitochondria, plastids

lished from the bacterial division. Bacterial cytokin- possess their own DNA which is organized by basic
esis occurs by invagination of the cell membrane as proteins to form nucleoids ( plastid nuclei) and plas-
soon as the bacterial nucleus has been replicated. tids are believed to be closely associated with the
Filamentous temperature-sensitive (fts) genes for evolution of eukaryotes [44]. Dynamic changes of
bacterial cytokinesis were originally identified in plastid nuclei have been examined during the life
Escherichia coli mutants collected in the late 1960s. cycle of algae and higher plants and the mechanism
Several proteins involved in bacterial protein recruit- of the condensation of plastid nuclei has been
ment to the division site in an FtsZ-dependent studied [45]. Plastid DNA (nuclei) is synthesized
manner had been identified, including FtsA, ZipA, during a specific phase of the division cycle. The
FtsK, FtsQ, FtsL, FtsI, FtsN and FtsW [37]. phases of the plastid division cycle consist of the
According to the endosymbiotic theory, mitochon- pt-S phase, the pt-G2 phase, the pt-M phase and
dria were derived from free-living α-proteobacteria the pt-G1 phase. During the pt-M phase, the division
that became engulfed by eukaryotic host cells. can be separated into two main events: division of
Mitochondria proliferate on their own during the cell the plastid nuclei and division of the stroma (the
cycle, in a manner similar to bacterial division. so-called plastid division or plastidkinesis). The
However, mitochondria have persisted within mechanism of plastid nuclear division is summar-
eukaryotic cells for a long period—approximately 1– ized below [45].
2 billion years. Since the organelle genome sizes, Plastid kinesis occurs after plastid nuclear div-
even in lower eukaryotes, are less than 10% of the ision and is similar to bacterial cytokinesis, based
size of the genomes found in free-living bacteria, it is on the evidence of the FtsZ protein which is
thought that following endosymbiosis, initially about involved in plastid division in Arabidopsis thaliana
90% of the endosymbiotic bacterial genes were trans- [46,47]. The fine structure and dynamics of the
ferred to the host cell nuclear genome, or lost plastid division ring (PD ring) provide the morpho-
entirely. As a consequence, only one FtsZ gene logical bases of plastid division [37,38]. Electron
remains as the mitochondrial dividing gene. Yoshida microscopic studies first identified a small
et al. [16] have now isolated the MD machinery and electron-dense ring at the constriction sites of divid-
identified a protein ZED that constricts the basal ing plastids in C. caldarium and subsequent studies
structure of the MD machinery with FtsZ (Fig. 4). have shown that similar structures are universally
ZED contains a mitochondrial transit signal and two present among the Bikonta [39]. However, in multi-
coiled-coil regions and has a partial homology with organelle algae and plants, it is difficult to examine
the bacterial division protein ZapA. In cytological the timing of each phase of the plastid division
studies, ZED was observed to accumulate to form a cycle because their organelles divide asynchro-
ring beneath the inner mitochondrial membrane and nously and the ring is too small to be studied.

Fig. 4 Immunofluorescent and electron microscope images showing ZED rings of mitochondria in C. merolae cells. (a–e) Phase contrast
immunofluorescence images of ZED (green) and mitochondrial matrix (red) through MD. (f–h) Phase contrast immunofluorescence images
show co-localization of ZED (green) and FtsZ (red). (i) Immuno-electron micrographs images of ZED. Immunogold particles (indicating ZED;
black arrowheads) are localized on the matrix side of the MD site. ( j, k) Model of the MD machinery and its component of ZED ring. ZED
interact with FtsZ1 to constitute the basal structure of MD machinery. This figure includes photographs that appeared in reference [16] (a–i), (k).
C. merolae was also employed to study the mor- period of 1 h during G2 phase ( pt-M), the plastid
phological changes during plastid division, and to nucleus elongated further and both ends of the
estimate its time course, using fluorescence imaging pt-nucleus were attached to the upper wall at oppo-
and the VIMPCS system [20], in live cells [21]. For site ends of the mother plastid. The inner com-
9 h during the early and middle G1 phase ( pt-G1), ponents of the plastid division machinery (FtsZ ring
the cup-shaped plastid with its central plastid and PD ring) were formed first, followed by the
nucleus became enlarged and, for about 1.5 h during outer components (outer PD ring and dynamin ring)
late G1 ( pt-S), it synthesized DNA. Over 2 h during S [38]. For 2 h during early M phase ( pt-M), the inner
phase ( pt-G2), the plastid enlarged further and and outer plastid division machinery contracted,
became peanut-shaped. The chloroplast nucleus pinching off the plastid at the division site and divid-
then elongated at one end and attached itself to the ing the mother plastid into two daughter plastids.
upper wall at one end of the chloroplast. Over a Plastid division was completed just before mitotic
metaphase. The plastid division machinery associ- clearly a key to solving the molecular mechanism
ated with the daughter plastids was released and of plastid division.
finally broken down. MD, microbody division,
mitosis and cytokinesis then follow in that order.
Division cycles and inheritance of
The mechanism of chloroplast division by the PD
single-membrane-bounded organelles
machinery has been reviewed by Kuroiwa et al.
(ER, Golgi apparatus, lysosomes and
[38,44].
microbodies)
Recently, our understanding of the process of
The inheritance of single-membrane-bounded, and
plastid division machinery has been advanced by
DNA-less organelles such as ER, Golgi bodies,
isolation of the PD machinery and by identification
vacuoles/lysosomes and microbodies, as well as of
of proteins and other components using MALDI–
double-membrane-bound organelles such as mito-
TOF–MS [14,15]. During chloroplast division, the
chondria and plastids, is an essential feature of
FtsZ ring (localized in the stroma), the PD ring
eukaryotic cell division.
(in the cytoplasm) and the dynamin ring (in the
cytoplasm) were formed in that order. The PD ring

is the main structural component of the PD Division cycle and inheritance of ER and Golgi
machinery and was observed to be a bundle of fine apparatus related to cell nucleus
filaments 5–7 nm in diameter. Two types of The behavior and inheritance of single-mem-brane-
guanosinetriphosphatase, a bacterially derived bounded organelles are related to the metabolism of
FtsZ and a eukaryote-specific dynamin, have been these organelles. mRNA is synthesized in the cell
characterized as PD-machinery-associated pro- nucleus and moves to the ER for translation.
teins. The isolation and analysis of the PD machin- Proteins are transported from ER to Golgi apparatus,
ery have been achieved and the complete which processes and packages both proteins and
sequencing of the genome has enabled proteomic lipids. Subsequently, these processes are aided by
analysis. To detect the components of the PD ring, the activities of lysosomes and microbodies.
Yoshida et al. [15,16] digested isolated PD machi- Therefore, the localization of these organelles is inti-
neries with various proteases but were unable to mately related to their functions established in their
completely decompose them. Therefore, they early evolution. In the primitive eukaryotes, the cell-
searched for hypothetical components that might nuclear division during mitosis is accompanied by
constitute the PD ring. Electron-dense deposits the inheritance of the ER and Golgi apparatus in
(indicating carbohydrates) appeared on the PD association with the mitotic spindle. By contrast, the
ring after staining with periodic acid–horseradish mitochondria are required as the dividing carrier of
peroxidase (PA-HRP). This suggested that the PD microbodies and lysosomes which are carried on the
ring might have a saccharic architecture. To mitochondrial spindle [20]. Therefore, we review
confirm this, we isolated PD machineries from that the inheritances of ER and Golgi apparatus are
dividing cells of C. merolae. Proteomic analysis in relation to the cell nucleus, while the inheritances
identified a protein, PDR1, a glycosyltransferase of microbodies and lysosomes are in relation to
which was present in the PD ring and is widely mitochondria. Although single-membrane-bounded
conserved from red alga to land plants (Fig. 5). organelles do not contain DNA, the division cycles
Electron microscopy showed that PDR1 forms a of these organelles are basically divided into several
ring with carbohydrates at the chloroplast-division phases: a phase of no growth, a phase of growth
site. Fluorometric saccharide ingredient analysis (synthesis of contents) and division, a phase of
of purified PD ring filaments showed that only migration to a carrier, such as a mitochondrion, and
glucose was included, and down-regulation of a phase of separation and release from the carrier.
PDR1 impaired chloroplast division. Thus, the As in many organisms, the cells contains numerous
chloroplasts are divided by the PD ring, which is a single-membrane-bounded organelles, it is difficult
bundle of PDR1-mediated polyglucan filaments. As to identify each of these phases. By contrast, in cells
thePDR-1 gene is universal in Bikonta [15], it is of C. merolae cell, which contain a minimum of

Fig. 5 Immunofluorescent and electron microscopyimages of PDR1 in C. merolae cells. (a–f ) Phase contrast immunofluorescence images of
PDR1 (green) and autofluorescence of plastids (red) through plastid division. (g) Electron microscopy using the PA-HRP method in a cell.
The PD machinery is stained black. Magnified image shows spectral colors correspondingto the intensity of staining signals of the region
around the PD ring (white arrowheads) (see color scales). cp, chloroplast. Scalebar, 2 μm. (h) Immuno-electron microscopy images of PDR1
in chloroplast division. Magnified image of the region around the PD ring (black arrowheads). n, nuclear; mt, mitochondria. Scale bar, 1 μm.
(i, j) Model of PD-machinery and PDR1 function. After the FtsZ ring (blue) is assembled (step 1), PDR1 proteins (red) are recruited at the
chloroplast division site and synthesize F-PDRs (PD ring filaments) (black) from UDP-glucose (step 2a). Other PDR1 proteins bind to
elongated F-PDRs and synthesize more F-PDRs (step 2b and step 3). This figure includes photographs that appeared in Ref. [15].
these organelles, it is possible to determine the formation, but during the binary division of the cell
approximate timing of these phases. nucleus [50]. The numerous Golgi apparatuses in
The ER and Golgi apparatus are directly con- the large unicellular green algae Micrasterias sp.
cerned with the functions of cell nucleus, their were located not only around cell nuclei, but also
behavior and their inheritance during cell cycle are, throughout the cytoplasm [51]. During the mitotic
therefore, intimately connected with those of the phase, their numbers increased from about 70 to
cell nucleus. Sheahan et al. [48] reported that 150 in Micrasterias pinnatifida, and from 200 to
during the division of the protoplasts of higher 400 in M. crux-melitensis. These additional Golgi
plants, the act in cytoskeleton was required for apparatuses, which were distributed throughout the
balanced inheritance of chloroplasts, mitochondria entire cytoplasm in M. pinnatifida [52] and
and ER. However, the genetic mechanism for the Closterium ehrenbergii [53], appeared synchro-
inheritance of the ER is unclear. nously at the premitotic stage. Noguchi [50] con-
By contrast, the division and inheritance of the cluded that Golgi apparatuses in plant and animal
Golgi apparatus (dictyosome) was cytologically cells divided during the M phase. The mother
examined in algae. The function of the Golgi appar- Golgi apparatus divided at the center from the cis
atus is to process and package proteins and lipids, side to the trans side to form daughter Golgi
particularly in the processing of proteins for apparatuses [54]. However, no special structure or
secretion. Noguchi [49] reviewed Golgi apparatus gene for this division has been identified. The
division cycles. In the alga Chlorococcum infusio- study with tobacco BY-2 cells showed that Golgi
num, the Golgi apparatus was localized close to the stacks, mitochondria and plastids sorted them-
cell nucleus. It was not duplicated during cell wall selves to distinct subcellular domains during
mitosis, but in an apparently cytoskeleton- organelles is large, their divisions are synchronized
independent manner [55,56]. as shown in Micrasterias [51].
The ER of C. merolae is much simpler than that Although there must be a molecular mechanism
of C. caldarium. It forms part of the nuclear envel- to control the relationship between these organelle
ope with attached ribosomes and did not disappear divisions and the cell nucleus, it is unknown.
during mitosis. This behavior is similar to that of
Saccharyomyces cerevisiae and Schizosacharo-
myces pombe [3]. Yagisawa et al. will report the be- Division behavior of lysosomes (vacuoles) and
havior of ER in detail during cell cycle in C. microbodies ( peroxisomes)
merolae using antibodies of DD genes. The mother As lysosomes and microbodies function more or
ER grows and develops during G1, S and G2 less independently from the synthetic function of
phases, divides with cell-nuclear division and is the cell nucleus, the division (inheritance) of these
inherited by the daughter cell-nuclear envelopes organelles is not directly related to the division of
during anaphase. A bridge between the inner and cell nuclei but to the division of mitochondria. The
outer membranes of the nuclear envelope occurs at functions of lysosomes and microbodies suggest

the division site of cell nucleus when mother cell that the origins of these organelles during eukary-
nucleus divides into daughter nuclei (Yagisawa F, otic evolution may have been later than that of the
Fujiwara T, Ohnuma M, Nishida K, Imoto Y, Yoshida ER and the Golgi apparatus. During inheritance
Y, Kuroiwa H and Kuroiwa T. unpublished data). (division, partition) of lysosomes and microbodies,
The molecular mechanism of ER inheritance (div- mitochondria are used as a carrier.
ision and separation) is unknown. Lysosomes and vacuoles are lytic compartments
C. merolae cell has a single Golgi apparatus with and they function as reservoirs for ions and metab-
few cisternae in the cytoplasm during the G1 phase olites, including pigments, and are crucial for the
[57], while unicellular green algae and plants processes of detoxification and general cell homeo-
contain more than 200 located around the cell stasis [58]. The vacuoles of algae, plants and yeasts
nucleus and throughout the cytoplasm [47]. share some of their basic properties with the lyso-
Although Noguchi [50,52] and Ueda [51] reported somes of animal cells [57]. In humans, loss of lysoso-
that the Golgi apparatus divided during the M phase mal function causes lysosomal storage disorders
and the premitotic stage, respectively; however, the such as Fabry disease and GM1 gangliosidosis [59].
mother Golgi apparatus in C. merolae divided into Recently, lysosomes have been actively studied as a
daughter Golgi apparatuses in the regions at the central organelle concerned with autophagy. The
two ends of the cell nucleus during late G1 phase main genes for autophagy, apg1-15, have been
and the daughters subsequently moved near to the actively studied in both yeast and animals [60].
centrosomes during the G2 phase (Yagisawa F, However, all of these genes were not encoded in the
Fujiwara T, Ohnuma M, Nishida K, Imoto Y, Yoshida C. merolae genome [9,12]. In mammals, plants and
Y, Kuroiwa H and Kuroiwa T. unpublished data). yeasts, lysosomes are inherited by the daughter cells
After cytokinesis, each daughter cell contained one [61–63]. In mammalian Madin–Darby canine kidney
Golgi apparatus. Although protein synthesis is (MDCK) cells, video and confocal microscopy ana-
required for division of the Golgi apparatus, its mol- lyses have showed that endosomes and lysosomes
ecular mechanism being unknown. remained intact and separated during mitosis. The
When the number of ER and Golgi apparatuses segregation into daughter cells took place by coordi-
per cell is small, the behavior of these organelles is nated movements, and the organelles accumulated
closely connected with the cell nucleus, which acts in the vicinity of the microtubule organization center
as a carrier. When there are a large number of during cytokinesis [61]. In plants, dynamic changes
these organelles, they are distributed through the in vacuoles during mitosis were examined by moni-
entire cytoplasm, as well as close to the cell toring the tubular structures of the vacuolar mem-
nucleus. Interestingly, even when the number of the brane (TVM) in living transgenic tobacco BY-2 cells
stably expressing GFP-AtVam3p. TVMs, which were (Fig. 6a). VIG1 appeared on the surface of free
initially organized from large vacuoles, elongated to vacuoles in the cytosol, and then tethered the vacu-
encircle the spindle at metaphase. Subsequently, the oles to the mitochondria by constructing net-like
TVMs invaded the equatorial region during anaphase structures. The vacuoles were released from the
to telophase, and were divided between the two mitochondrion in the daughter cells following VIG1
daughter cells by the cell plate at cytokinesis. digestion. Inhibition of VIG1 by cycloheximide or
Furthermore, actin filaments were indispensable for antisense RNA disturbed the migration of the vacu-
the development and maintenance of TVMs [62]. oles and they were unequally inherited by the
However, the molecular mechanisms of lysosome daughter cells. VIG1 is essential for vacuole inheri-
inheritance were not revealed. During vacuole tance in C. merolae. Since VIG1 is conserved
inheritance in S. cerevisiae, the vacuole formed ves- among eukaryotes, VIG1 may regulate the inheri-
icular–tubular projections known as segregation tance of eukaryote lysosome and vacuoles. The
structures. The segregation structures originated growth and division of the vacuoles occurred
from the vacuole membrane and extended to the during G1 and S phases. Separation of the (approxi-
daughter bud. This inheritance was based on an mately) six daughter lysosomes occurred during G2

actin cable and myosin-V motor protein Myo2 and M phases after moving toward and attachment
withVac8 and Vac17 [63,64]. The Myo2-Vac8-Vac17 to the mitochondrion. After completion of MD, the
complex drives the segregation structures of the vacuoles remained attached to the daughter mito-
vacuole to the bud along the act in cable. chondria for more than 1 h before being released
In the C. merolae cell, there are no actin or [10,17].
myosin filaments. Lysosomes are inherited by Microbodies ( peroxisomes) are spherules,
daughter cells by binding to the dividing mitochon- 0.5–2.0 μm in diameter, and are characterized by
drion through a small electron-dense bridge the presence of the enzyme catalase, which pro-
[9,10,65]. No functional actin filaments have been tects the cell from oxidative stress, such as that
detected by immunological methods or by staining caused by peroxide produced following the
with rhodamine-conjugated phalloidin [32]. A single exposure of cellular metabolites to high concen-
act in gene was encoded in the C. merolae genome, trations of molecular oxygen. Microbodies play a
but not expressed, while no myosin gene was role in β-oxidation of fatty acids. They are present
present [9]. Therefore, a currently unknown mech- in a wide variety of eukaryotic cells, including
anism that does not depend on actin filaments must Amoebozoa, Bikonts and Opisthokonts. The
be involved in vacuole inheritance. Moreover, mam- number of microbodies ranges from 1 per cell in
malian, plant and yeast cells contain many orga- primitive organisms like C. merolae to between 10
nelles whose divisions occur at random, and and 1000 per cell in Bikonts and Opisthokonts.
organelles with diverse and complicated shapes Microbody functions are relatively independent
[38]. In these cells, the movements of organelles is from the cell nucleus they do not associate with
not entirely understood. the cell nucleus. Microbodies, like mitochondria
As described above, C. merolae cell is expected and plastids, are believed to be organelles of bac-
to provide unique tools for resolving the issue of terial origin [66,67]. However, a microbody division
lysosome inheritance. Recently, Fujiwara et al. gene of bacterial origin is not yet known in the
studied vacuole inheritance ( partition and separ- eukaryotes. Microbodies are believed to have been
ation) during mitosis. Genes involved in this acquired by primitive eukaryotic cells by endosym-
process were identified by gene expression profiling biotic phagocytosis of a prokaryote ( probably an
[17]. C. merolae contained about three vacuoles that aerobic Gram-positive bacterium such as Listeria
were equally inherited by the daughter cells by or Mycoplasma), which has eventually lost its
binding to dividing mitochondria. The binding was DNA. This may explain why microbodies behave
mediated by a novel30-kDa coiled-coil protein more independently from the cell nucleus than the
(vacuole inheritance gene 1, VIG1), identified by other single-membrane-bounded organelles. In an
microarray analyses and immunological assays earlier review, we considered that after the

Fig. 6 Division mechanisms of lysosomes (vacuoles) and microbodies ( peroxisomes). (a) Immunofluorescent and electron
microscopyimages of VIG1 in C. merolae cells. (a) Phase contrast immunofluorescence images of VIG1 (green) and lysosome (red) through
cell cycle. Scale bar, 2 μm (b) Immuno-electron microscopy images of VIG1 in MD. Magnified image of the vacuole region shows binding to
the mitochondrial membrane. vc, vacuole; mt, mitochondria; pt, plastid. Scale bar, 200 nm. (c) Model for vacuole inheritance in C. merolae.
VIG1 accumulates at patch structures on the vacuolar surface in the cytosol. The patch structures have an asymmetric distribution during
S phase. During M phase, the VIG1 patch localizes between the vacuole membrane and mitochondrial surface and tethers the vacuole to the
mitochondria. After cytokinesis, digestion of VIG1 allows the vacuole tore turn to the cytosol. This figure includes photographs that appeared
in Ref. [17] (a–c). (b)Immunofluorescent and electron microscopy images showing segregation of microbodies in C. merolae cells. (a, b)
Phase contrast immunofluorescence images of division of microbodies (green), mitochondria (red) and α-tubulin (blue) at M phase (a) and
cytokinesis (b). Segregating microbodies are in contact with daughter mitochondria (white double arrowheads). (c–e) Electron micrographs
of thin sections of C. merolae cells at M phase (c) and cytokinesis (d). Magnified view of the contact site between a microbody and the
mitochondrion of a cell at the same stage as (d), (e). Electron-dense apparatuses were observed between the microbodies and mitochondria
(black double arrowheads). *or arrowheads, microbodies; cp, chloroplast; mt, mitochondrion. Scale bar, 2 μm (a, b), 500 nm (c, d), 100 nm
(e). (f ) Model for microbody segregation during M phase and cytokinesis in C. merolae. Microbodies bind to centrioles through mitochondria
and electron-dense apparatus. Electron-dense apparatus between the microbody and the mitochondrion play a role in segregating the
microbodies during M phase and cytokinesis, and correspond to the kinetochore of mitotic chromosome division. This figure includes
photographs that appeared in Refs. [21] (c) and [65] (d, e).
bacterial ancestor entered the eukaryote cell, it There have been many investigations into the
lost its DNA and the bacterial cell membrane, and mechanism of division (inheritance) of microbodies.
eventually the bacterial matrix and the interspace A relationship has been reported between microbo-
between the outer and inner envelopes became dies in animal cells and division genes [38].
mixed into the putative pre-microbody [38]. Generally, microbody divisions in mammalian cells,
trypanosomes, yeasts and algae progress in the mitochondrion throughout its proliferation cycle,
order of elongation, constriction and fission. The except in G1 phase cells, and was entwined around
combined efforts of several research groups have the divisional plane of the mitochondrion during
identified 32PEX genes that contribute to the biogen- the MD. Immunocytochemical labeling of catalase
esis or maintenance of microbodies. Microbody div- as a marker of matrix proteins of the microbody
ision involved the conserved PEX 11 membrane revealed that the duplication of catalase occurred
proteins and, in yeast, was shown to require a in tandem with the volume increase. The growth
dynamin-like protein. PEX11 and two PEX11-related phase of the microbody occurred over about 50 min
proteins were the predominant membrane proteins during G2 and early prophase. The microbody div-
of the microbodies of Trypanosoma brucei and it ision phase occurred over a period of about 130
was concluded that the PEX11 family of proteins min from the M phase after completion of MD to
played important roles in determining microbody cytokinesis. Thus, microbody was spherical for
membrane structure [68]. Higher level expression of about 16 h in G1 phase.
Pex11pb promotedmicrobody division in mamma- The PEX11 and Fis1p genes were not encoded in
lian cells [69]. Dynamin-like protein 1 (DLP1), which the C. merolae genome and thus these proteins

is essential for MD, was recently reported to also be were never visualized at the division site of the
involved in microbody division [70] and was microbody. However, Miyagishima et al. [65] ident-
recruited to microbodies in part by PEX11. Li and ified an electron-dense apparatus, 30–50 nm in
Gould [71] showed that DLP1, the human homolog diameter, between the microbody and the mito-
of the yeast DNM1 and VPS genes, played an impor- chondrion, which might play a role in segregating
tant role in microbody division in human cells. In the microbodies corresponding to the kinetochores
addition, Fis1p also was found in microbodies. In of mitotic chromosomes. Therefore, microbodies
conjunction with DLP1, it appears to support the were bound to spindle pole bodies through mito-
fission not only of mitochondria, but also of micro- chondria [20] (Fig. 6b). Finally, microbodies divided
bodies [70]. Fts1 plays important roles in microbody by binary fission after constriction at their equators.
division and the maintenance of microbody mor- The composition of putative microbody division
phology in mammalian cells, possibly in a concerted machinery responsible for dividing the microbody
manner together with Pex11pb and DLP1 [72]. at the division site has not been determined.
However, PEX, dynamin-like proteins, and Fis1p Therefore, the mitochondrion might play a role in
have not been visualized at the division site of micro- separating the daughter microbodies.
bodies so that the mechanism of division is still These results clearly showed that two daughter
unclear. microbodies arose by binary fission of the pre-
In C. merolae cells, there is a single spherical existing mother microbody. In animal cells, it is
microbody which facilitates observation of its believed that PEX11 and Fis1 are involved in micro-
dynamic behavior during cell cycle. Miyagishima body division. However, PEX11 and Fis1 genes for
et al. [65] reported that, during the early and middle the microbody division were not encoded in C.
G1 phases, the microbody was located in the cyto- merolae genome. It seems that the genes for MD
plasm. During late G1 and S phases, the microbody induced the microbody division indirectly by means
moved toward its carrier, the mitochondrion, and of the electron dense disc-shaped apparatus.
attached to it. In the M phase of C. merolae cells,
the mitochondrion and the associated microbody
assumed a characteristic sequence of shapes (in Cytoskelton and spindle
order: rod, worm, branched, H-shaped, dumb-bell), Cytoskeletal proteins play a major role in the cell
and symmetric fission occurred just before cytokin- transport system and in division during the mitotic
esis. The microbody doubled its volume in M phase cycle so that it is important to examine their
and three-dimensional quantitative analysis revealed dynamics during the cell cycle. Higher eukaryotes
that its surface area increased before its volume did possess complex microtubule systems and a large
[65]. The microbody was in contact with the number of organelles. In contrast, in C. merolae,
two actin genes are not expressed [9,40], the spindle poles for about 1 h during the G2 phase.
myosin gene is absent from the genome [9,12], only Mitochondrial spindles appeared during M phase
five kinesin motor proteins are expressed [9], and ( prophase) taking about 200 min. Mitotic spindles
microtubules are only present when they are orga- were formed over a period of about 2 h from meta-
nized to form spindles during mitosis [40]. These phase to the completion of cytokinesis.
unique systems in primitive eukaryotes suggest that
microtubule systems first evolved in association
with the mitotic apparatus and that the cytoskeletal Reciprocal relationships among
or transport systems seen in higher eukaryotes the organelles
were acquired later. Microtubules are fundamentally The origin of eukaryotic host cells is still unclear,
important cytoskeletal elements for nuclear and but it is now generally accepted that mitochondria
organelle division. and plastids arose from endosymbiosis of
C. merolae serves as a model system for the α-proteobacteria and cyanobacteria-like photosyn-
study of general mechanisms of proliferation of the thetic bacteria, respectively. Many of the genes of
cell nucleus and of organelles. Imoto et al. [20] these endosymbionts, including those for DNA

have characterized the relationships between the replication and for the maintenance of genomic
mitotic, mitochondrial, plastid and microbody div- integrity, were subsequently lost or transferred to
ision cycles and, using microfluorometry and the nuclear genome by endosymbiotic gene trans-
cytochemical techniques, have demonstrated the fer. According to the current dogma, the transfer of
involvement of microtubules and spindle poles in genes of endosymbiotic origin to the cell nucleus
these processes. C. merolae cells demonstrated five that are required for organelle DNA replication
discrete stages of microtubule dynamics: (1) the (ODR) has resulted in loss of the independence of
microtubules disappeared during the G1 phase; (2) the cell cycles of the endosymbionts and in their
α-tubulin was dispersed within the cytoplasm integration into the eukaryotic control system that
without forming microtubules during the S phase; is mediated largely by cyclins and cyclin-dependent
(3) α-tubulin was assembled into spindle poles kinase. However, coordination of cell cycle, events
during the G2 phase; (4) polar microtubules were such as DNA replication would have been essential
organized along the mitochondrion during pro- for establishing the integrity of eukaryotic cells, at
phase; and (5) mitotic spindles in cell nuclei were least during the early stages of endosymbiotic
organized during the M phase. Microfluorometry association.
demonstrated that the location of the intensity peak Although there is little evidence for discrete cell-
corresponding to α-tubulin changed in the following cycle control of ODR in animal and fungal cells,
sequence: spindle poles, mitochondria, spindle studies using algae and flowering plants have shown
poles and central spindle area. However, the total that ODR precedes the subsequent cell proliferation
fluorescent intensity did not change markedly cycles composed of cell nuclear DNA synthesis and
throughout the mitotic phases, suggesting that div- cell division. The advantage of studying cell nuclear
ision and separation of the cell nucleus and mito- and organelle proliferation cycles in C. merolae is
chondrion were mediated by the spindle pole that cell division can be highly synchronized by
bodies. Inhibition of microtubule organization dark–light cycles. Initiation of the cell cycle by illu-
induced inhibitions of cell-nuclear division, mito- mination in combination with microscopic quantifi-
chondrial separation, and division of the single cation of organelle DNA content revealed that ODR
membrane-bound microbody, implying that, besides always occurs before cell nuclear DNA replication
cell-nuclear division, mitochondrial separation and (NDR) [36]. After completion of both ODR and NDR,
microbody division were also dependent on micro- division of the plastid, mitochondrion and cell
tubules. In the case of centrosomes, the duplication nucleus occurs sequentially and is followed by cyto-
phase probably occurred over about 2 h during S kinesis. However, the mechanism by which replica-
phase. The mother centrosomes were separated tion of three genomes with different origins is
into two and α-tubulin was assembled into the coordinated is largely unknown. Kobayashi et al.

Fig. 7 Summary of the reciprocal relationships among the double membrane-bounded organelles (cell nucleus, mitochondrion and plastid),
single membrane-bounded organelles (ER, Golgi apparatus, vacuoles/lysosomes and microbody) and non-membrane-bounded organelle
(centrosome). Bold lines indicate cell nucleus–organelle regulations. Division of the mitochondria, plastids and centrosomes are directly
regulated by the cell nucleus through the MD/PD machineries or cytoskeletal proteins such as tubulin. Continuous thick lines indicate
organelle–cell nucleus or organelle–organelle regulations. NDR depends on ODR and is regulated by a tetrapyrrole signal which activates
CDKA in plant cells. Division of the cell nucleus and separation of mitochondria is regulated by centrosomes through mitotic spindles and
mitochondrial spindles. Lysosomes/vacuoles are equally inherited by the daughter cells by interaction with dividing mitochondria mediated
by VIG1. In segregating the microbodies, an electron-dense apparatus, 30–50 nm in diameter, between the microbody and the mitochondrion,
might play an important role. Dashed line shows probable relationships suggested in the present study. Organelle–cell nucleus coupling and
organelle–organelle coupling also seem to have a role in the proliferation of the double-, single-, and non-membrane-bounded organelles.
[73] showed that, in plant cells, NDR was regulated ODR. These observations thus show that tetrapyr-
by a tetrapyrrolesignal, which has been suggested to role-mediated organelle–nucleus replicational coup-
be an organelle-to-nucleus retrograde signal. In ling was an evolutionary conserved process among
synchronized cultures of C. merolae, specific inhi- plant cells.
bition of A-type cyclin-dependent kinase (CDKA) Single-membrane-bounded organelles (ER, Golgi
prevented NDR but not ODR after onset of the cell apparatus, vacuoles/lysosomes microbodies) must
cycle [73]. In contrast, inhibition of ODR by nalidixic originally have had their own division cycles, as
acid also resulted in inhibition of NDR, indicating a implied by current cytological and morphological
strict dependence of NDR on ODR. The requirement knowledge. Physical attachment and metabolic con-
for ODR to precede NDR was circumvented by nection between organelles are now achieved
addition of the tetrapyrrole intermediates protopor- through interactions between them, such as a mito-
phyrin IX (ProtoIX) or Mg-ProtoIX, both of which chondrion–vacuole interaction mediated by the
activated CDKA without inducing ODR. This scheme coiled-coil protein VIG1 [17], and a fatty
was also observed in cultured tobacco BY-2 cells, acidβ-oxidation system which coexists within and
where inhibition of ODR by nalidixic acid prevented cooperates between mitochondria and microbodies
CDKA activation and NDR, and these inhibitions [74,75]. These physical and metabolic connections
were circumvented by Mg-ProtoIX without inducing may have developed into the tight reciprocal nets
among proliferation cycles in multi-organelle cells Funding

in algae, animals and plants. This work was supported by grants from Scientific
Centrosomes are well-known non-mem-brane- Research on Priority Areas (no. 19207004 to T.K.),
bounded organelles, which regulate the positioning the Frontier Project ‘Adaptation and Evolution of
and transportation of the other double- and Extremophiles’ from the Ministry of Education,
single-membrane-bounded organelles through the Culture, Sports, Science and Technology of Japan,
cytoskeleton [76] and the movement of the cell and by the program for the Promotion of Basic
nucleus by the mitotic spindles. In primitive eukar- Search Activities for Innovative Biosciences
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Article in Journal of electron microscopy · August 2011

Yuuta Imoto Fumi Yagisawa

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Introduction of the cell cycle are generally understood to corre-

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orthogonal centrosomes separate. In general, in organelles, and of non-membrane-bounded orga-

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