Malena, A;
Pantic, B;
Borgia, D;
Sgarbi, G;
Solaini, G;
Holt, IJ;
Spinazzola, A;
... Vergani, L; + view all
(2016)
Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA.
Autophagy
, 12
(11)
pp. 2098-2112.
10.1080/15548627.2016.1226734.
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Spinazzola_Malena et al. Cell type mtQC-m3243G mutation .pdf - Accepted Version Download (871kB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1080/15548627.2016.1226734 |
| Publisher version: | http://doi.org/10.1080/15548627.2016.1226734 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | A549.B2 adenocarcinoma cells, autophagy, mitochondria, mitochondrial dynamics, mitochondrial quality control, mitophagy, mutation-m3243G, pathological mtDNA, RD.Myo rhabdomyosarcoma cells |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1546408 |
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