Pervasive within-Mitochondrion Single-Nucleotide Variant Heteroplasmy as Revealed by Single-Mitochondrion Sequencing

Morris, Jacqueline; Na, Young-Ji; Zhu, Hua; Lee, Jaehee; Giang, Hoa; Ulyanova, Alexandra V.; Baltuch, Gordon H.; Brem, Steven; Chen, H. Isaac; Kung, David; Lucas, Timothy H.; O’Rourke, Donald M.; Wolf, John A.; Grady, M. Sean; Sul, Jai‐Yoon; Kim, Junhyong; Eberwine, James

doi:10.1016/j.celrep.2017.11.031

Cited by 53 publications

(76 citation statements)

References 34 publications

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“…At first, analysis of a single mitochondrion was limited by the technological resolution of mutational detection (Reiner et al, 2010). However, a recent study investigated mtDNA sequence variation within 118 isolated mitochondria from mouse neurons and astrocytes (Morris et al, 2017). Whole mtDNA sequencing of each of the isolated mitochondria revealed an average of 3.9 (± 5.71 SD) single heteroplasmic nucleotide variants (SNVs) in the tested mitochondrial population per nucleotide position.…”

Section: Selection Acts On the Phenotype-the Various Levels Of Mitochmentioning

confidence: 99%

The Mitochondrial Genome–on Selective Constraints and Signatures at the Organism, Cell, and Single Mitochondrion Levels

Shtolz

2019

Front. Ecol. Evol.

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Natural selection acts on the phenotype. Therefore, many mistakenly expect to observe its signatures only in the organism, while overlooking its impact on tissues, cells and subcellular compartments. This is particularly crucial in the case of the mitochondrial genome (mtDNA), which, unlike the nucleus, resides in multiple cellular copies that may vary in sequence (heteroplasmy) and quantity among tissues. Since the mitochondrion is a hub for cellular metabolism, ATP production, and additional activities such as nucleotide biosynthesis and apoptosis, mitochondrial dysfunction leads to both tissue-specific and systemic disorders. Therefore, strong selective pressures act to maintain mitochondrial function via removal of deleterious mutations via purifying (negative) selection. In parallel, selection also acts on the mitochondrion to allow adaptation of cells and organisms to new environments and physiological conditions (positive selection). Nevertheless, unlike the nuclear genetic information, the mitochondrial genetic system incorporates closely interacting bi-genomic factors (i.e., encoded by the nuclear and mitochondrial genomes). This is further complicated by the order of magnitude higher mutation rate of the vertebrate mtDNA as compared to the nuclear genome. Such mutation rate difference generates a generous mtDNA mutational landscape for selection to act, but also requires tight mito-nuclear co-evolution to maintain mitochondrial activities. In this essay we will consider the unique mitochondrial signatures of natural selection at the organism, tissue, cell, and single mitochondrion levels.

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Section: Selection Acts On the Phenotype-the Various Levels Of Mitochmentioning

confidence: 99%

The Mitochondrial Genome–on Selective Constraints and Signatures at the Organism, Cell, and Single Mitochondrion Levels

Shtolz

2019

Front. Ecol. Evol.

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“…Future experimental studies quantifying the importance of selective mitophagy under physiological conditions would be beneficial for understanding heteroplasmy variance dynamics. The ubiquity of heteroplasmy (Morris et al, 2017;Payne et al, 2012;Ye et al, 2014) suggests that a neutral drift approach to mitochondrial genetics may be justified, which contrasts with the studies of Tam et al (2013Tam et al ( , 2015 and Mouli et al (2009) which focus purely on the selective effects of mitochondrial networks.…”

Section: Discussionmentioning

confidence: 99%

“…Our basic approach therefore also differs from previous modelling attempts, since our model is neutral with respect to genetics (no replicative advantage or selective mitophagy) and the mitochondrial network (no selective fusion). Evidence for negative selection of particular mtDNA mutations has been observed in vivo (Morris et al, 2017;Ye et al, 2014); we therefore extend our analysis to explore selectivity in the context of mitochondrial quality control using our simplified framework.…”

Section: Introductionmentioning

confidence: 97%

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.

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“…Morris et al, in their study on single mitochondrion mtDNA deep sequencing originating from neural tissue in both mouse and human, were able to demonstrate several populations of mtDNA within the same cell. They showed extensive intracellular heteroplasmy with a significant percentage of mtDNA harbouring single nucleotide variance with potentially detrimental effects on mitochondrial function [58].…”

Section: Mitochondrial Dynamics -Fusion and Fissionmentioning

confidence: 99%

The Role of Mitochondria in Oocyte and Early Embryo Health

Kim¹,

Kenigsberg²,

Jurisicova³

et al. 2019

obm genet

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The mitochondria of the oocyte are a prominent source of energy metabolism as well as mitochondrial DNA that will later populate the cells of the offspring. Recent discoveries provided new insight into the physiology of the mitochondria and its unique genetics. The concept of heteroplasmy defined as the presence of more than one type of mitochondrial genome, is gaining increasing recognition as an important contributor to several complex morbidities, age-related reproductive dysfunction and aging. Understanding the changes caused by pathogenic mutations as well as identifying defects occurring during reproductive aging will enhance our knowledge of the role of mitochondria as organelles in germ cell biology. In this review, we summarize the current state of knowledge about the role of mitochondria in embryo and fetal development.

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Pervasive within-Mitochondrion Single-Nucleotide Variant Heteroplasmy as Revealed by Single-Mitochondrion Sequencing

Cited by 53 publications

References 34 publications

The Mitochondrial Genome–on Selective Constraints and Signatures at the Organism, Cell, and Single Mitochondrion Levels

The Mitochondrial Genome–on Selective Constraints and Signatures at the Organism, Cell, and Single Mitochondrion Levels

Mitochondrial network state scales mtDNA genetic dynamics

The Role of Mitochondria in Oocyte and Early Embryo Health

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