Sepsis is associated with mitochondrial DNA damage and a reduced mitochondrial mass in the kidney of patients with sepsis-AKI

Abstract

Background Sepsis is a life-threatening condition accompanied by organ dysfunction subsequent to a dysregulated host response to infection. Up to 60% of patients with sepsis develop acute kidney injury (AKI), which is associated with a poor clinical outcome. The pathophysiology of sepsis-associated AKI (sepsis-AKI) remains incompletely understood, but mitochondria have emerged as key players in the pathogenesis. Therefore, our aim was to identify mitochondrial damage in patients with sepsis-AKI. Methods We conducted a clinical laboratory study using “warm” postmortem biopsies from sepsis-associated AKI patients from a university teaching hospital. Biopsies were taken from adult patients (n = 14) who died of sepsis with AKI at the intensive care unit (ICU) and control patients (n = 12) undergoing tumor nephrectomy. To define the mechanisms of the mitochondrial contribution to the pathogenesis of sepsis-AKI, we explored mRNA and DNA expression of mitochondrial quality mechanism pathways, DNA oxidation and mitochondrial DNA (mtDNA) integrity in renal biopsies from sepsis-AKI patients and control subjects. Next, we induced human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS) for 48 h to mimic sepsis and validate our results in vitro. Results Compared to control subjects, sepsis-AKI patients had upregulated mRNA expression of oxidative damage markers, excess mitochondrial DNA damage and lower mitochondrial mass. Sepsis-AKI patients had lower mRNA expression of mitochondrial quality markers TFAM, PINK1 and PARKIN, but not of MFN2 and DRP1. Oxidative DNA damage was present in the cytosol of tubular epithelial cells in the kidney of sepsis-AKI patients, whereas it was almost absent in biopsies from control subjects. Oxidative DNA damage co-localized with both the nuclei and mitochondria. Accordingly, HUVECs induced with LPS for 48 h showed an increased mnSOD expression, a decreased TFAM expression and higher mtDNA damage levels. Conclusion Sepsis-AKI induces mitochondrial DNA damage in the human kidney, without upregulation of mitochondrial quality control mechanisms, which likely resulted in a reduction in mitochondrial mass.

Targeting Oxidative Stress in Septic Acute Kidney Injury: From Theory to Practice

“…Thus, mitochondrial fission, followed by fusion, in this case, is seemingly an important adaptive reparative process because it not only arrests mitochondrial damage, but also prevents excessive loss of mitochondrial mass, thereby limiting ROS-induced injury. Supporting this notion, decreased expression of both mitochondrial PINK1 and Parkin mRNA has been reported in biopsies derived from patients who succumbed to severe septic AKI [91]. ).…”

“…This mediates the release of cytochrome c, which in turn interacts with apoptotic protease activating factor-1 proteins, ultimately forming an apoptosome that triggers a procaspase-9-mediated downstream intrinsic apoptosis cascade [92,93] (Figure 3). This process facilitates the removal of whole mitochondria in severe sepsis and results in a reduction of mitochondrial mass [91], which can further compromise the production of host antioxidants and enhance the production of superoxide (Figure 3). Therefore, ROS-induced damage to the mitochondria in sepsis can result in enhanced ROS production and accumulation, which can contribute to the vicious propagating cycle of oxidative stress, microvascular injury and cellular injury, culminating in AKI.…”

Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice

“…With regard to self-DNA, sepsis also induces mitochondrial damage, and host cell death enhances free mtDNAs and nDNAs that could be exposed to cytosolic cGAS, thereby facilitating sepsis hyperinflammation in a vicious cycle [ 37 ]. Subsequently, severe sepsis inflammation, partly due to cGAS activation, causes further cell death, which more prominently elevates free mtDNA [ 38 , 39 ]. Then, cfDNA, from either bacteria or host cells, might affect sepsis severity, so that the manipulation of cfDNA in sepsis could have beneficial effects.…”

Sepsis and the Risks of Long-Term Renal Adverse Outcomes in Patients With Chronic Kidney Disease

“…The possible explanations for the impact of sepsis on worsened renal outcomes are likely to be multifactorial. Sepsis may trigger inflammatory cascades through the release of inflammatory mediators, and the upregulation of reactive oxygen species may induce DNA damage and protein structure alteration and trigger fibrogenic processes, resulting in kidney injury and CKD development (36)(37)(38). In addition, sepsis and hemodynamic instability may contribute to acute tubular necrosis and glomerular injury resulting from deposition of circulating immune complexes, which cause macrophage infiltration and oxidative stress damage (39)(40)(41).…”