Dynamics of Mitochondria during the Cell Cycle

Abstract

As well as the classic bean-shaped structures observed in electron micrographs, mitochondria are frequently found as long, snake-shaped tubules, and extended reticular networks whose overall morphology depends on the balance of fission and fusion of mitochondrial tubules in growing cells. [1][2][3][4] Such mitochondrial morphology, size, distribution, and copy number were demonstrated to change in living cells during cellular differentiation, development, or under pathological conditions, including liver disease, muscle dystrophy, cardiomyopathy, and cancer. [5][6][7] In differentiated cells, mitochondria are often localized to specific cytoplasmic regions rather than randomly distributed. 8) Additionally, mitochondrial morphology and distribution changed by the metabolic state of the cell or during cell growth. [9][10][11][12] Although the role of mitochondria in metabolism, ATP production, and apoptosis is more widely recognized, alterations in mitochondrial morphology and abundance are also important for cellular functions. In fact, the distribution of mitochondria in dendrites of living hippocampal neurons, which are regulated by mitochondrial fission/fusion, has been shown to be an essential and limiting factor for synapse density and plasticity. 13) Detail, however, on the mitochondrial behaviour during cellular differentiation and cell cycle progression in higher eukaryotes has little been revealed.It was shown that at S-phase, there is a substantial increase in the amount of phosphorylated histone H1 and that the phosphorylated histone H1 is diffusely distributed throughout the cell nucleus.14) On the other hand, at the end of Sphase, phosphorylation of histone H3 begins immediately following the replication of the centromeric heterochromatin.15) This phosphorylation is diffusely distributed throughout the nucleus, but, initiating at the centromers, spreads throughout the genome as the cells progress to prophase. Thus, when used in combination, staining with antibodies to phosphorylated histone H1 and H3 can be used to clearly and easily resolve mixed cell populations into each of the major stages of the cell cycle (UPSTATE, 2002 Catalog, Technical Appendix pp. 365).In the present study, we investigated mitochondrial dynamics during the cell cycle progression using synchronized HeLa cells in which the cells were transfected with mitoDsRed1 to visualize mitochondria in the cells and the major stages of the cell cycle of the observed cells were resolved by staining the cells with phosphorylated histone H1 and H3 antibodies. We found that mitochondria exist as filamentous network structures throughout the cell cycle progression, changing their morphology, distribution, and abundance. MATERIALS AND METHODS Double-Thymidine Block and Cell Cycle AnalysisHeLa cells were maintained in Dulbecco's modified Eagle's medium (DMEM; GIBCO Invitrogen Corp., Carlsbad, CA, U.S.A.) plus 10% fetal calf serum at 37°C under an atmosphere of 5% CO 2 . Cells were synchronized for the G1/S boundary by a double-thymidine block p...

Cell cycle-dependent mitochondrial biogenesis and dynamics in mammalian cells

“…Cell cycle-dependent morphological changes of mitochondria were first reported by Arakaki et al [20]. We also showed that mitochondria exist as highly inter-connected tubular structures or long spiral forms of tubules during interphase but undergo a drastic reorganization upon mitotic entry.…”

The novel conserved mitochondrial inner-membrane protein MTGM regulates mitochondrial morphology and cell proliferation

“…Several recent reports have shown that changes in mitochondrial morphology occur during cell division (Arakaki et al, 2006;Lee et al, 2007) and that Drp1 is phosphorylated by Cdk1-cyclin B in this process (Taguchi et al, 2007). We show that overexpression of MTGM results in mitochondrial fragmentation, stalling of cells in S-phase-associated DNA damage indicated by γ-H2AX staining, and exclusion of cells from mitosis, whereas depletion of MTGM results in mitochondrial elongation and cell-cycle progression.…”

“…These processes not only control the shape of mitochondria but also affect many cellular functions (Chan, 2006;Grandemange et al, 2009;Knott et al, 2008;Suen et al, 2008). Several recent studies reported that morphological changes of mitochondria occur during cell division (Arakaki et al, 2006;Lee et al, 2007). Mitochondria present as interconnected tubular structures in interphase, undergo a drastic reorganization and fragmentation at an early mitotic stage, and finally reform tubular structures in the two daughter cells.…”

A hyperfused mitochondrial state achieved at G 1 –S regulates cyclin E buildup and entry into S phase

“…Although attempts have been made to investigate this question (7,8), no study has been conclusive enough to determine whether changes in mitochondrial morphology are determinant of any cell cycle stage. These cell cycle stages include a long growth phase (G 1 ), a DNA replicating phase (S), a short growth phase (G 2 ), and cell division (mitosis, M).…”