Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila

Kandul, Nikolay P.; Zhang, Ting; Hay, Bruce A.; Guo, Ming

doi:10.1038/ncomms13100

Cited by 89 publications

(94 citation statements)

References 70 publications

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“…1). The balance of mitochondrial fusion and ssion is critical for the normal physiological function of cells, which contribute to regulation of mitochondrial morphology [11,12] , exchange of content [13,14] , maintenance of mitochondrial DNA (mtDNA) [9,15] and clearance of damaged mitochondria [16,17] . Defect and damage in mitochondrial dynamics have resulted in numerous human diseases, such as Charcot-Marie-Tooth disease type 2A (CMT2A) [18,19] , Multiple symmetric lipomatosis [20,21] , Dominant optic atrophy [22] , Microcephaly and Optic atrophy [23] .…”

Section: Introductionmentioning

confidence: 99%

The Status and Trends of Mitochondrial Dynamics Research: A Global Bibliometric and Visualized Analysis

Mao

Liu

et al. 2020

Preprint

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Objectives: Mitochondria are remarkably dynamic organelles encapsulated by bilayer membranes. The dynamic properties of mitochondria are critical for energy production. Our study aims to investigate the global status and trends of mitochondrial dynamics research.Method: Publications related to the studies of mitochondrial dynamics from 2000 to 2019 were retrieved from Web of Science database. A total of 2999 publications were included. Bibliometric analysis was conducted by visualization of similarities viewer and GraphPadPrism 5 software.Results: There is an increasing trend of mitochondrial dynamics research during the last 20 years. The cumulative number of publications about mitochondrial dynamics research followed the logistic growth model Ob . The USA made the highest contributions to the global research. The journal Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease had the largest publication numbers. The Johns Hopkins University is the most contributive institution. The main research orientation and funding agency were cell biology and NIH. All keywords related studies could be divided into three clusters: “Related disease research”, “Mechanism research” and “Cell metabolism research”.Conclusion: Attention should be drawn to the latest popular research and more efforts will be put into mechanistic research, which may inspire new clinical treatments for the associated diseases.

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Section: Introductionmentioning

confidence: 99%

The Status and Trends of Mitochondrial Dynamics Research: A Global Bibliometric and Visualized Analysis

Mao

Liu

et al. 2020

Preprint

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“…If mitophagy is able to change mean heteroplasmy, then a neutral genetic model appears to be inappropriate, as mutants experience a higher rate of degradation. Biological examples of non-neutral behavior include the observation that the PINK1/Parkin pathway can select against deleterious mtDNA mutations in vitro (Suen et al 2010) and in vivo (Kandul et al 2016), as has repression of the mTOR pathway via treatment with rapamycin (Dai et al 2013;Kandul et al 2016). However, the necessity of performing a genetic/pharmacological intervention to clear mutations via this pathway suggests that the ability of tissues to selectively remove mitochondrial mutants under physiological conditions is weak.…”

Section: Discussionmentioning

confidence: 99%

“…If we assume that fusion is selective in favor of wild-type mtDNAs, which appears to be the case at least for some mutations under therapeutic conditions (Suen et al 2010;Kandul et al 2016), we predict that a balance between fusion and fission is the most effective means of removing mutant mtDNAs (see below), perhaps explaining why mitochondrial networks are often observed to exist as balanced between mitochondrial fusion and fission (Sukhorukov et al 2012;Zamponi et al 2018). In contrast, if selective mitophagy pathways are induced then promoting fragmentation is predicted to accelerate the clearance of mutants (see below).…”

Section: Control Strategies Against Mutant Expansionsmentioning

confidence: 99%

Mitochondrial Network State Scales mtDNA Genetic Dynamics

et al. 2019

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Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may also be associated with healthy aging. mtDNA is stochastically replicated and degraded, and exists within organelles which undergo dynamic fusion and fission. The role of the resulting mitochondrial networks in the time evolution of the cellular proportion of mutated mtDNA molecules (heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy variance), remains incompletely understood. Heteroplasmy variance is particularly important since it modulates the number of pathological cells in a tissue. Here, we provide the first wide-reaching theoretical framework which bridges mitochondrial network and genetic states. We show that, under a range of conditions, the (genetic) rate of increase in heteroplasmy variance and de novo mutation are proportionally modulated by the (physical) fraction of unfused mitochondria, independently of the absolute fission-fusion rate. In the context of selective fusion, we show that intermediate fusion:fission ratios are optimal for the clearance of mtDNA mutants. Our findings imply that modulating network state, mitophagy rate, and copy number to slow down heteroplasmy dynamics when mean heteroplasmy is low could have therapeutic advantages for mitochondrial disease and healthy aging. KEYWORDS mitochondrial DNA; mitochondrial networks; heteroplasmy variance; cellular noise M ITOCHONDRIAL DNA (mtDNA) encodes elements of the respiratory system vital for cellular function. Mutation of mtDNA is one of several leading hypotheses for the cause of normal aging (López-Otín et al. 2013; Kauppila et al. 2017), as well as underlying a number of heritable mtDNArelated diseases (Schon et al. 2012). Cells typically contain hundreds, or thousands, of copies of mtDNA per cell: each molecule encodes crucial components of the electron transport chain, which generates energy for the cell in the form of ATP. Consequently, the mitochondrial phenotype of a single cell is determined, in part, by its fluctuating population of mtDNA molecules (Wallace and Chalkia 2013; Stewart and Chinnery 2015; Aryaman et al. 2019; Johnston 2019). The broad biomedical implications of mtDNA mutation, combined with the countable nature of mtDNAs and the stochastic nature of their dynamics, offer the opportunity for mathematical understanding to provide important insights into human health and disease (Aryaman et al. 2019). An important observation in mitochondrial physiology is the threshold effect, whereby cells may often tolerate relatively high levels of mtDNA mutation until the fraction of mutated mtDNAs (termed heteroplasmy) exceeds a certain critical value where a pathological phenotype occurs (Rossignol et al. 2003; Picard et al. 2014; Stewart and Chinnery 2015; Aryaman et al. 2017). Fluctuations within individual cells mean that the fraction of mutant mtDNAs per cell is not constant within a tissue (Figure 1A), but follows a probability distribution which changes with time

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“…If mitophagy is able to change mean heteroplasmy, then a neutral genetic model appears to be inappropriate, as mutants experience a higher rate of degradation. Stimulation of the PINK1/Parkin pathway has been shown to select against deleterious mtDNA mutations in vitro (Suen et al, 2010) and in vivo (Kandul et al, 2016), as has repression of the mTOR pathway via treatment with rapamycin (Dai et al, 2013;Kandul et al, 2016). However, the necessity of performing a genetic/pharmacological intervention to clear mutations via this pathway suggests that the ability of tissues to selectively remove mitochondrial mutants under physiological conditions is weak.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial network state scales mtDNA genetic dynamics

Aryaman

Bowles

Jones

et al. 2018

Preprint

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Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may also be associated with healthy aging. MtDNA is stochastically replicated and degraded, and exists within organelles which undergo dynamic fusion and fission. The role of the resulting mitochondrial networks in the time evolution of the cellular proportion of mutated mtDNA molecules (heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy variance), remains incompletely understood. Heteroplasmy variance is particularly important since it modulates the number of pathological cells in a tissue. Here, we provide the first wide-reaching theoretical framework which bridges mitochondrial network and genetic states. We show that, under a range of conditions, the (genetic) rate of increase in heteroplasmy variance and de novo mutation are proportionally modulated by the (physical) fraction of unfused mitochondria, independently of the absolute fission-fusion rate. In the context of selective fusion, we show that intermediate fusion/fission ratios are optimal for the clearance of mtDNA mutants. Our findings imply that modulating network state, mitophagy rate and copy number to slow down heteroplasmy dynamics when mean heteroplasmy is low could have therapeutic advantages for mitochondrial disease and healthy aging.

show abstract

Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila

Cited by 89 publications

References 70 publications

The Status and Trends of Mitochondrial Dynamics Research: A Global Bibliometric and Visualized Analysis

The Status and Trends of Mitochondrial Dynamics Research: A Global Bibliometric and Visualized Analysis

Mitochondrial Network State Scales mtDNA Genetic Dynamics

Mitochondrial network state scales mtDNA genetic dynamics

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