title: Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA.
abstract: Pathological mutations in the mitochondrial DNA (mtDNA) produce a diverse range of tissue-specific diseases and the proportion of mutant mitochondrial DNA can increase or decrease with time via segregation, dependent on the cell or tissue type. Previously we found that adenocarcinoma (A549.B2) cells favored wild-type (WT) mtDNA, whereas rhabdomyosarcoma (RD.Myo) cells favored mutant (m3243G) mtDNA. Mitochondrial quality control (mtQC) can purge the cells of dysfunctional mitochondria via mitochondrial dynamics and mitophagy and appears to offer the perfect solution to the human diseases caused by mutant mtDNA. In A549.B2 and RD.Myo cybrids, with various mutant mtDNA levels, mtQC was explored together with macroautophagy/autophagy and bioenergetic profile. The 2 types of tumor-derived cell lines differed in bioenergetic profile and mitophagy, but not in autophagy. A549.B2 cybrids displayed upregulation of mitophagy, increased mtDNA removal, mitochondrial fragmentation and mitochondrial depolarization on incubation with oligomycin, parameters that correlated with mutant load. Conversely, heteroplasmic RD.Myo lines had lower mitophagic markers that negatively correlated with mutant load, combined with a fully polarized and highly fused mitochondrial network. These findings indicate that pathological mutant mitochondrial DNA can modulate mitochondrial dynamics and mitophagy in a cell-type dependent manner and thereby offer an explanation for the persistence and accumulation of deleterious variants.
authors.affiliation: a Department of Neurosciences , University of Padova , Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Malena
authors.affiliation: a Department of Neurosciences , University of Padova , Italy.
authors.forename: Boris
authors.initials: B
authors.lastname: Pantic
authors.affiliation: a Department of Neurosciences , University of Padova , Italy.
authors.forename: Doriana
authors.initials: D
authors.lastname: Borgia
authors.affiliation: b Department of Biomedical and Neuromotor Sciences , University of Bologna , Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sgarbi
authors.affiliation: b Department of Biomedical and Neuromotor Sciences , University of Bologna , Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Solaini
authors.affiliation: c Medical Research Council, Mill Hill Laboratory , London , United Kingdom.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Holt
authors.affiliation: c Medical Research Council, Mill Hill Laboratory , London , United Kingdom.
authors.forename: Antonella
authors.initials: A
authors.lastname: Spinazzola
authors.affiliation: d Department of Cardiac, Thoracic and Vascular Sciences, Biostatistics, Epidemiology and Public Health Unit , University of Padova , Padova , Italy.
authors.forename: Egle
authors.initials: E
authors.lastname: Perissinotto
authors.affiliation: e Department of Biomedical Sciences , University of Padova , Italy.|f Venetian Institute of Molecular Medicine , Padova , Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.affiliation: b Department of Biomedical and Neuromotor Sciences , University of Bologna , Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baracca
authors.affiliation: a Department of Neurosciences , University of Padova , Italy.
authors.forename: Lodovica
authors.initials: L
authors.lastname: Vergani
mesh_terms: D000072283:A549 Cells; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D004734:Energy Metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009840:Oligomycins / Q000494:pharmacology; D000071456:Sequestosome-1 Protein / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009840:Oligomycins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein
keywords: A549.B2 adenocarcinoma cells; RD.Myo rhabdomyosarcoma cells; autophagy; mitochondria; mitochondrial dynamics; mitochondrial quality control; mitophagy; mutation-m3243G; pathological mtDNA