title: Mitochondrial genome regulates mitotic fidelity by maintaining centrosomal homeostasis.
abstract: 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.
authors.affiliation: Department of Biology; Georgia State University; Atlanta, GA USA.
authors.forename: Shashikiran
authors.initials: S
authors.lastname: Donthamsetty
authors.affiliation: Department of Biology; Georgia State University; Atlanta, GA USA.
authors.forename: Meera
authors.initials: M
authors.lastname: Brahmbhatt
authors.affiliation: Department of Biology; Georgia State University; Atlanta, GA USA.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Pannu
authors.affiliation: Department of Biology; Georgia State University; Atlanta, GA USA.
authors.forename: Padmashree C G
authors.initials: PC
authors.lastname: Rida
authors.affiliation: Department of Biology; Georgia State University; Atlanta, GA USA.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Ramarathinam
authors.affiliation: Department of Biology; Georgia State University; Atlanta, GA USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Ogden
authors.affiliation: Department of Biology; Georgia State University; Atlanta, GA USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Departments of Genetics, Pathology, and Environmental Health and Center for Free Radical Biology, Center for Aging, and UAB Comprehensive Cancer Center; University of Alabama at Birmingham; Birmingham, AL USA and Birmingham Veterans Affairs Medical Center; Birmingham, AL USA.
authors.forename: Keshav K
authors.initials: KK
authors.lastname: Singh
authors.affiliation: Department of Biology; Georgia State University; Atlanta, GA USA.
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018385:Centrosome / Q000378:metabolism*; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D015536:Down-Regulation; D042967:Electron Transport Complex I / Q000378:metabolism; D054629:Genome, Mitochondrial / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D008938:Mitosis / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D042967:Electron Transport Complex I
keywords: centrosome amplification; cybrid; mitochondrial genome; osteosarcoma; rho0