Mitochondrial genome regulates mitotic fidelity by maintaining centrosomal homeostasis

Mitochondrial genome regulates mitotic fidelity by maintaining centrosomal homeostasis

Centrosomes direct spindle morphogenesis to assemble a bipolar mitotic apparatus to enable error-free chromosome segregation and preclude chromosomal instability (CIN). Amplified centrosomes, a hallmark of cancer cells, set the stage for CIN, which underlies malignant transformation and evolution of...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Vol. 13; no. 13; pp. 2056 - 2255
Main Authors: Donthamsetty, Shashikiran, Brahmbhatt, Meera, Pannu, Vaishali, Rida, Padmashree, Ramarathinam, Sujatha, Ogden, Angela, Cheng, Alice, Singh, Keshav K., Aneja, Ritu
Format: Journal Article
Language:English
Published: United States Taylor & Francis 01-07-2014
Landes Bioscience
Subjects:
Cell Line, Tumor
Cell Proliferation
Centrosome - metabolism
centrosome amplification
cybrid
DNA Damage
DNA, Mitochondrial - metabolism
Down-Regulation
Electron Transport Complex I - metabolism
Genome, Mitochondrial - physiology
Homeostasis
Humans
mitochondrial genome
Mitosis - genetics
osteosarcoma
Reactive Oxygen Species - metabolism
rho0
Spindle Apparatus - metabolism
Telomere - ultrastructure
Tumor Suppressor Protein p53 - metabolism
centrosome amplification
mitochondrial genome
rho0
cybrid
osteosarcoma
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Summary:Centrosomes direct spindle morphogenesis to assemble a bipolar mitotic apparatus to enable error-free chromosome segregation and preclude chromosomal instability (CIN). Amplified centrosomes, a hallmark of cancer cells, set the stage for CIN, which underlies malignant transformation and evolution of aggressive phenotypes. Several studies report CIN and a tumorigenic and/or aggressive transformation in mitochondrial DNA (mtDNA)-depleted cells. Although several nuclear-encoded proteins are implicated in centrosome duplication and spindle organization, the involvement of mtDNA encoded proteins in centrosome amplification (CA) remains elusive. Here we show that disruption of mitochondrial function by depletion of mtDNA induces robust CA and mitotic aberrations in osteosarcoma cells. We found that overexpression of Aurora A, Polo-like kinase 4 (PLK4), and Cyclin E was associated with emergence of amplified centrosomes. Supernumerary centrosomes in rho0 (mtDNA-depleted) cells resulted in multipolar mitoses bearing "real" centrosomes with paired centrioles at the multiple poles. This abnormal phenotype was recapitulated by inhibition of respiratory complex I in parental cells, suggesting a role for electron transport chain (ETC) in maintaining numeral centrosomal homeostasis. Furthermore, rho0 cells displayed a decreased proliferative capacity owing to a G 2 /M arrest. Downregulation of nuclear-encoded p53 in rho0 cells underscores the importance of mitochondrial and nuclear genome crosstalk and may perhaps underlie the observed mitotic aberrations. By contrast, repletion of wild-type mtDNA in rho0 cells (cybrid) demonstrated a much lesser extent of CA and spindle multipolarity, suggesting partial restoration of centrosomal homeostasis. Our study provides compelling evidence to implicate the role of mitochondria in regulation of centrosome duplication, spindle architecture, and spindle pole integrity.
Bibliography:These authors contributed equally to this work.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.29061