bims-mitper Biomed News
on Mitochondrial Permeabilization
Issue of 2023–05–28
two papers selected by
Bradley Irizarry, Thomas Jefferson University
  1. The Fate of Oxidative Strand Breaks in Mitochondrial DNA.
  2. Associations between circulating cell-free mitochondrial DNA, inflammatory markers, and cognitive and physical outcomes in community dwelling older adults.
  1. Antioxidants (Basel). 2023 May 12. pii: 1087. [Epub ahead of print]12(5):
    The Fate of Oxidative Strand Breaks in Mitochondrial DNA.
    Genevieve Trombly, Afaf Milad Said, Alexei P Kudin, Viktoriya Peeva, Janine Altmüller, Kerstin Becker, Karl Köhrer, Gábor Zsurka, Wolfram S Kunz.
      Mitochondrial DNA (mtDNA) is particularly vulnerable to somatic mutagenesis. Potential mechanisms include DNA polymerase γ (POLG) errors and the effects of mutagens, such as reactive oxygen species. Here, we studied the effects of transient hydrogen peroxide (H2O2 pulse) on mtDNA integrity in cultured HEK 293 cells, applying Southern blotting, ultra-deep short-read and long-read sequencing. In wild-type cells, 30 min after the H2O2 pulse, linear mtDNA fragments appear, representing double-strand breaks (DSB) with ends characterized by short GC stretches. Intact supercoiled mtDNA species reappear within 2-6 h after treatment and are almost completely recovered after 24 h. BrdU incorporation is lower in H2O2-treated cells compared to non-treated cells, suggesting that fast recovery is not associated with mtDNA replication, but is driven by rapid repair of single-strand breaks (SSBs) and degradation of DSB-generated linear fragments. Genetic inactivation of mtDNA degradation in exonuclease deficient POLG p.D274A mutant cells results in the persistence of linear mtDNA fragments with no impact on the repair of SSBs. In conclusion, our data highlight the interplay between the rapid processes of SSB repair and DSB degradation and the much slower mtDNA re-synthesis after oxidative damage, which has important implications for mtDNA quality control and the potential generation of somatic mtDNA deletions.
    Keywords:  mitochondrial DNA; mtDNA degradation; mtDNA double-strand breaks mtDNA single-strand breaks; oxidative damage
    DOI:  https://doi.org/10.3390/antiox12051087
  2. Immun Ageing. 2023 May 23. 20(1): 24
    Associations between circulating cell-free mitochondrial DNA, inflammatory markers, and cognitive and physical outcomes in community dwelling older adults.
    Lolita S Nidadavolu, Danielle Feger, Diefei Chen, Yuqiong Wu, Francine Grodstein, Alden L Gross, David A Bennett, Jeremy D Walston, Esther S Oh, Peter M Abadir.
       BACKGROUND: Dementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has been proposed as an immune stimulator and potential predictor of mortality in acute illnesses. Dementia and frailty are both associated with mitochondrial dysfunction, impaired cellular energetics, and cell death. The size and abundance of ccf-mtDNA fragments may indicate the mechanism of cell death: long fragments typically result from necrosis, while short fragments arise from apoptosis. We hypothesize that increased levels of necrosis-associated long ccf-mtDNA fragments and inflammatory markers in serum are linked to declines in cognitive and physical function, as well as increased mortality risk.
    RESULTS: Our study of 672 community-dwelling older adults revealed that inflammatory markers (C-Reactive Protein, soluble tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 [sTNFR1], and interleukin-6 [IL-6]) positively correlated with ccf-mtDNA levels in serum. Although cross-sectional analysis revealed no significant associations between short and long ccf-mtDNA fragments, longitudinal analysis demonstrated a connection between higher long ccf-mtDNA fragments (necrosis-associated) and worsening composite gait scores over time. Additionally, increased mortality risk was observed only in individuals with elevated sTNFR1 levels.
    CONCLUSION: In a community dwelling cohort of older adults, there are cross-sectional and longitudinal associations between ccf-mtDNA and sTNFR1 with impaired physical and cognitive function and increased hazard of death. This work suggests a role for long ccf-mtDNA as a blood-based marker predictive of future physical decline.
    Keywords:  Cell-free DNA; Dementia; Frailty; Inflammation; Mitochondria; sTNFR1
    DOI:  https://doi.org/10.1186/s12979-023-00342-y
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