Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging

Lujan, Scott A.; Longley, Matthew J.; Humble, Margaret H.; Lavender, Christopher A.; Burkholder, Adam; Blakely, Emma L.; Alston, Charlotte L.; Gorman, Gráinne; Turnbull, D.M.; McFarland, Robert; Taylor, Robert W.; Kunkel, Thomas A.; Copeland, William C.

doi:10.1186/s13059-020-02138-5

Cited by 60 publications

(55 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One possibility is the accumulation of heteroplasmic mitochondrial genome deletions or point mutations that could prevent or attenuate PCR primer recognition ( 21 ). Heteroplasmic DNA deletions have been repeatedly demonstrated to accumulate with age within the MT-COX3 gene ( 22 – 24 ), and to a lesser degree, within the MT-CYTB locus, due to age-related defects of mitochondrial DNA polymerase proofreading capability ( 25 , 26 ).…”

Section: Discussionmentioning

confidence: 99%

Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19

Scozzi¹,

Cano²,

Ma³

et al. 2021

JCI Insight

130

110

View full text Add to dashboard Cite

Background Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined. Methods We measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19. Results Circulating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had a similar or superior area under the curve when compared against clinically established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy. Conclusion These results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes. Funding Washington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345.

show abstract

Section: Discussionmentioning

confidence: 99%

Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19

Scozzi¹,

Cano²,

Ma³

et al. 2021

JCI Insight

130

110

View full text Add to dashboard Cite

show abstract

“…The observed deletions are likely to originate from an incomplete duplication of mtDNA resulting in a chimeric molecule, the full-length sequence conferring the replication origins lacking in the deleted sequence, as already hypothesized by others [ 37 ]. Such rearrangements have already been described in human tumors and the aging process [ 35 , 36 , 38 ].…”

Section: Discussionmentioning

confidence: 91%

“…Class I deletions are driven by DNA–polymerase–gamma defaults, while class III deletions, found in 74% of cases in our study, are more frequently associated with the aging process [ 35 , 36 ]. Furthermore, half of the deletions encompassed one or the two origins of replication, which questions how these molecules replicate and thus could be detected.…”

Section: Discussionmentioning

confidence: 95%

Mitochondrial DNA Instability Is Common in HIV-Exposed Uninfected Newborns

Monnin

Desquiret-Dumas

Méda

et al. 2021

JCM

View full text Add to dashboard Cite

Worldwide, one million HIV-exposed uninfected (HEU) children are born yearly, and chronic health impairments have been reported in these children. Mitochondrial DNA (mtDNA) instability and altered mtDNA content have been evidenced in these children, but an exhaustive characterization of altered mitochondrial genomes has never been reported. We applied deep mtDNA sequencing coupled to the deletion identification algorithm eKLIPse to the blood of HEU neonates (n = 32), which was compared with healthy controls (n = 15). Dried blood spots (DBS) from African HEU children were collected seven days after birth between November 2009 and May 2012. DBS from French healthy controls were collected at birth (or <3 days of life) in 2012 and in 2019. In contrast to the absence of mtDNA instability observed at the nucleotide level, we identified significant amounts of heteroplasmic mtDNA deletions in 75% of HEU children and in none of controls. The heteroplasmy rate of the 62 mtDNA deletions identified varied from 0.01% to up to 50%, the highest rates being broadly compatible with bioenergetic defect and clinical expression. mtDNA integrity is commonly affected in HEU neonates. The nature of the deletions suggests a mechanism related to aging or tumor-associated mtDNA instability. This child population may be at risk of additional mtDNA genetic alterations considering that they will be exposed to other mitotoxic drugs including antiretroviral or anti-tuberculosis treatment.

show abstract

“…However, maternal age is also a factor, which is more difficult to explain. Although outside the scope of this review, whole mitochondrial genome sequencing studies also show age-dependent increases in both point mutations [ 29 ] and large deletions [ 30 ]. The situation is even more extreme in large, long-lived hyphal fungi [ 31 , 32 ] and trees [ 33 , 34 , 35 , 36 , 37 ].…”

Section: Nuclear Mutation Rates Trends In Mmr-proficient Organismsmentioning

confidence: 99%

Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair

Lujan

Kunkel

2021

Cells

Self Cite

View full text Add to dashboard Cite

We describe the contribution of DNA mismatch repair (MMR) to the stability of the eukaryotic nuclear genome as determined by whole-genome sequencing. To date, wild-type nuclear genome mutation rates are known for over 40 eukaryotic species, while measurements in mismatch repair-defective organisms are fewer in number and are concentrated on Saccharomyces cerevisiae and human tumors. Well-studied organisms include Drosophila melanogaster and Mus musculus, while less genetically tractable species include great apes and long-lived trees. A variety of techniques have been developed to gather mutation rates, either per generation or per cell division. Generational rates are described through whole-organism mutation accumulation experiments and through offspring–parent sequencing, or they have been identified by descent. Rates per somatic cell division have been estimated from cell line mutation accumulation experiments, from systemic variant allele frequencies, and from widely spaced samples with known cell divisions per unit of tissue growth. The latter methods are also used to estimate generational mutation rates for large organisms that lack dedicated germlines, such as trees and hyphal fungi. Mechanistic studies involving genetic manipulation of MMR genes prior to mutation rate determination are thus far confined to yeast, Arabidopsis thaliana, Caenorhabditis elegans, and one chicken cell line. A great deal of work in wild-type organisms has begun to establish a sound baseline, but far more work is needed to uncover the variety of MMR across eukaryotes. Nonetheless, the few MMR studies reported to date indicate that MMR contributes 100-fold or more to genome stability, and they have uncovered insights that would have been impossible to obtain using reporter gene assays.

show abstract

Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging

Cited by 60 publications

References 104 publications

Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19

Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19

Mitochondrial DNA Instability Is Common in HIV-Exposed Uninfected Newborns

Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair

Contact Info

Product

Resources

About