Inhibition of mitochondrial fission favours mutant over wild-type mitochondrial DNA

Malena, Adriana; Loro, Emanuele; Re, Miriam Di; Holt, Ian; Vergani, Lodovica

doi:10.1093/hmg/ddp281

Cited by 85 publications

(60 citation statements)

References 58 publications

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“…[21][22][23][24] However, there was no significant difference of autophagy flux between heteroplasmic A549.B2 and RD.Myo cells and actually we observed the opposite of what expected. In fact, autophagy flux was slightly higher in RD.Myo than in A549.B2 during accumulation of mutated mtDNA.…”

Section: Discussioncontrasting

confidence: 76%

“…Consistently, a genetically induced fusion mimics and accelerates a similar physiological process. 21 Another key element in modulating mitochondrial dynamics is the redox state. Fusion is induced by oxidized glutathione 77,78 and regulated by the redox-sensing protein ROMO1.…”

Section: Discussionmentioning

confidence: 99%

“…[21][22][23] We used 3 0% A549.B2 and 3 0% RD.Myo clones; one A549.B2 and one RD.Myo clone with 100% m3243G mtDNA; heteroplasmic A549.B2 clones: one with 35%, one with 70%, one with 80% m3243G mtDNA; heteroplasmic RD.Myo clones: one with 70% and one with 80% m3243G mtDNA. Cells were grown in Dulbecco's modified Eagle's medium (4500 mg glucose/l, 110 mg pyruvate/l) (Gibco-ThermoFisher Scientific, 41966-029), supplemented with 10% fetal bovine serum (FBS; Gibco-ThermoFisher Scientific, 10270-106), amino acids (Gibco-ThermoFisher Scientific, 11130-036), L-glutamine (Sigma-Aldrich, G5763), vitamins (Biochrom, K0373), amphotericin B (Bristol Myers-Squibb, 6116) and antibiotics (Biochrom, A2213).…”

Section: Cell Culturementioning

confidence: 99%

“…After 22 h, cells were collected and the DNA was extracted, as described previously. 21 In each sample the mtDNA copy number was quantified by SYBR Green (Life Technologies-ThermoFisher Scientific, 11733-046), quantitative real-time PCR, using the ABI PRISM 7000 sequence detection system (Applied Biosystem-ThermoFisher Scientific, Foster City, CA, USA). The mtDNA copy number was related to the AR (androgen receptor) gene.…”

Section: Molecular Analysismentioning

confidence: 99%

“…[17][18][19][20][21][22][23][24] Generally, in the same individual mutant mtDNA molecules accumulate in tissues, such as muscle, brain, heart; the opposite of what occurs in blood and lung where mutant load is lower. [17][18][19][20] In line with in vivo results, we found that mutated mtDNA was accumulated in RD.Myo cybrids, 21,22 while WT mtDNA was selected in A549.B2 cybrids. 23,24 A better understanding of the molecular mechanisms underpinning the selection of mutant or wild-type mtDNA would provide new therapeutic approaches for mitochondrial diseases that are currently largely incurable.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

et al. 2016

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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.

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Section: Discussioncontrasting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Molecular Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

et al. 2016

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Functional organization of mammalian mitochondrial DNA in nucleoids: History, recent developments, and future challenges

2009

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SummaryVarious proteins involved in replication, repair, and the structural organization of mitochondrial DNA (mtDNA) have been characterized in detail over the past 25 or so years. In addition, in recent years, many proteins were identified with a role in the dynamics of the mitochondrial network. Using advanced imaging and an increasing number of cytological techniques, we have begun to realize that an important aspect to mtDNA maintenance, in both health and disease, is its organization within the dynamic mitochondrial network in discrete protein-DNA complexes usually termed nucleoids. Here, I review recent developments in the study of nucleoid dynamics and proteins. I will discuss the implications of the organization of mtDNA in nucleoids in light of DNA replication, repair, gene expression, segregation, and inheritance.

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Mitochondrial DNA and primary mitochondrial dysfunction in Parkinson's disease

et al. 2017

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In 1979, it was observed that parkinsonism could be induced by a toxin inhibiting mitochondrial respiratory complex I. This initiated the long-standing hypothesis that mitochondrial dysfunction may play a key role in the pathogenesis of Parkinson's disease (PD). This hypothesis evolved, with accumulating evidence pointing to complex I dysfunction, which could be caused by environmental or genetic factors. Attention was focused on the mitochondrial DNA, considering the occurrence of mutations, polymorphic haplogroup-specific variants, and defective mitochondrial DNA maintenance with the accumulation of multiple deletions and a reduction of copy number. Genetically determined diseases of mitochondrial DNA maintenance frequently manifest with parkinsonism, but the age-related accumulation of somatic mitochondrial DNA errors also represents a major driving mechanism for PD. Recently, the discovery of the genetic cause of rare inherited forms of PD highlighted an extremely complex homeostatic control over mitochondria, involving their dynamic fission/fusion cycle, the balancing of mitobiogenesis and mitophagy, and consequently the quality control surveillance that corrects faulty mitochondrial DNA maintenance. Many genes came into play, including the PINK1/parkin axis, but also OPA1, as pieces of the same puzzle, together with mitochondrial DNA damage, complex I deficiency and increased oxidative stress. The search for answers will drive future research to reach the understanding necessary to provide therapeutic options directed not only at limiting the clinical evolution of symptoms but also finally addressing the pathogenic mechanisms of neurodegeneration in PD. © 2017 International Parkinson and Movement Disorder Society.

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Inhibition of mitochondrial fission favours mutant over wild-type mitochondrial DNA

Cited by 85 publications

References 58 publications

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

Functional organization of mammalian mitochondrial DNA in nucleoids: History, recent developments, and future challenges

Mitochondrial DNA and primary mitochondrial dysfunction in Parkinson's disease

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