Association between oxidized nucleobases and mitochondrial DNA damage with long-term mortality in patients with sepsis

Elisabeth C van der Slikke; Bastiaan S Star; Vincent M Quinten; Jan C Ter Maaten; Jack J M Ligtenberg; Matijs van Meurs; Ron T Gansevoort; Stephan J L Bakker; Mu-Rong Chao; Robert H Henning; Hjalmar R Bouma

doi:10.1016/j.freeradbiomed.2021.12.305

Association between oxidized nucleobases and mitochondrial DNA damage with long-term mortality in patients with sepsis

Free Radic Biol Med. 2022 Feb 1:179:156-163. doi: 10.1016/j.freeradbiomed.2021.12.305. Epub 2021 Dec 21.

Affiliations

¹ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, the Netherlands.
² Department of Emergency Medicine, University of Groningen, University Medical Center Groningen, the Netherlands.
³ Department of Internal Medicine, University of Groningen, University Medical Center Groningen, the Netherlands.
⁴ Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁵ Department of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands.
⁶ Department of Occupational Safety and Health, Chung Shan Medical University, Taichung, Taiwan; Department of Occupational Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
⁷ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, the Netherlands; Department of Internal Medicine, University of Groningen, University Medical Center Groningen, the Netherlands. Electronic address: h.r.bouma@umcg.nl.

PMID: 34952158
DOI: 10.1016/j.freeradbiomed.2021.12.305

Abstract

Background: Sepsis not only leads to short-term mortality during hospitalization, but is also associated with increased mortality during long-term follow-up after hospital discharge. Metabolic stress during sepsis may cause oxidative damage to both nuclear and mitochondrial DNA (mtDNA) and RNA, which could affect long-term health and life span. Therefore, the aim of this study was to assess the association of sepsis with oxidized nucleobases and (mt)DNA damage and long-term all-cause mortality in septic patients.

Methods: 91 patients with sepsis who visited the emergency department (ED) of the University Medical Center Groningen between August 2012 and June 2013 were included. Urine and plasma were collected during the ED visit. Septic patients were matched with 91 healthy controls. Death rate was obtained until June 2020.The degree of oxidation of DNA, RNA and free nucleobases were assessed in urine by mass-spectrometry. Lipid peroxidation was assessed in plasma using a TBAR assay. Additionally, plasma levels of mtDNA and damage to mtDNA were determined by qPCR.

Results: Sepsis patients denoted higher levels of oxidated DNA, RNA, free nucleobases and lipid peroxidation than controls (all p < 0.01). Further, sepsis patients displayed an increase in plasma mtDNA with an increase in mtDNA damage compared to matched controls (p < 0.01). Kaplan meier survival analyses revealed that high degrees of RNA- and nucleobase oxidation were associated with higher long-term all-cause mortality after sepsis (p < 0.01 and p = 0.01 respectively). Of these two, high RNA oxidation was associated with long-term all-cause mortality, independent of adjustment for age, medical history and sepsis severity (HR 1.29 [(1.17-1.41, 95% CI] p < 0.01).

Conclusions: Sepsis is accompanied with oxidation of nuclear and mitochondrial DNA and RNA, where RNA oxidation is an independent predictor of long-term all-cause mortality. In addition, sepsis causes mtDNA damage and an increase in cell free mtDNA in plasma.

Keywords: Long-term mortality; Mitochondrial DNA; Nucleic acids oxidation; Oxidative stress; Sepsis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA Damage
DNA, Mitochondrial* / genetics
Humans
Mitochondria
Prospective Studies
Sepsis*

Substances

DNA, Mitochondrial