Decoding mitochondrial DNA damage and repair associated with H. pylori infection

Abstract

Mitochondrial genomic stability is critical to prevent various human inflammatory diseases. Bacterial infection significantly increases oxidative stress, driving mitochondrial genomic instability and initiating inflammatory human disease. Oxidative DNA base damage is predominantly repaired by base excision repair (BER) in the nucleus (nBER) as well as in the mitochondria (mtBER). In this review, we summarize the molecular mechanisms of spontaneous and H. pylori infection-associated oxidative mtDNA damage, mtDNA replication stress, and its impact on innate immune signaling. Additionally, we discuss how mutations located on mitochondria targeting sequence (MTS) of BER genes may contribute to mtDNA genome instability and innate immune signaling activation. Overall, the review summarizes evidence to understand the dynamics of mitochondria genome and the impact of mtBER in innate immune response during H. pylori-associated pathological outcomes.

Keywords: H. pylori; Type I interferon response; base excision DNA repair; cGAS-STING; cytosolic DNA; genomic instability; innate immune signaling; mitochondrial DNA damage and repair.

Figure 1

Oxidative stress induced by H. pylori infection leads to damage in mitochondrial DNA (mtDNA), which is primarily repaired through the base excision repair (BER) pathway. The BER pathway operates through two different mechanisms to maintain the mitochondrial genome: short-patch BER (SP-BER) removes a single damaged nucleotide, while long-patch BER (LP-BER) removes between two and eight damaged nucleotides during the repair process. H. pylori infection induces genotoxin-mediated mtDNA and increases oxidative-stress-associated mtDNA damage and mtDNA replication stress. A single-base damage or single-strand break on mtDNA is likely processed via BER. mtDNA single-base damage is potentially recognized and removed by one of the DNA glycosylases (UNG1, OGG1, MUTHY MTH1, NTHL1 NEIL1, and NEIL2), followed by end processing via the dRP lyase activity of POLB and gap filling with POLG inserts in the correct base, and LIGII seals the mtDNA nick. In long-patch BER, strand displacement DNA synthesis is processed by POLG and displaces 5′ DNA flap downstream of the repair site, which must be removed by flap endonuclease (FEN1) and other partner/DNA2/EXOG involved to process the 5′ end of the DNA. Once tailoring of the 5′ and 3′ ends of mtDNA is complete, LIGIII seals the mtDNA nick. Figure created with BioRender.com.

Figure 2

H. pylori-mediated mitochondrial dysfunction and inflammation. Upon infection, H. pylori secretes toxins such as VacA, which interacts with the mitochondria, leading to the modulation of its function and ultimately promoting pathogenesis. It decreases the mitochondrial membrane potential, leading to reduced ATP production and an increase in cytochrome c release that triggers autophagy. Additionally, VacA enhances the mtDNA damage and the generation of ROS. This triggers a series of stress responses, including the upregulation of mitochondrial DNA repair mechanism factors (e.g., POLG and TFAM) and the activation of the cGAS/STING pathway due to the release of damaged mtDNA and nDNA in the cytosol. Cells have a mechanism to respond to unrepaired mtDNA damages that includes trans-lesion synthesis, fusion, fission, and mitophagy that degrades severely damaged mitochondria. The accumulation of ROS and the release of mitochondrial contents also activate the NLRP3 inflammasome, leading to the processing and release of pro-inflammatory cytokines IL-1β and IL-18. Collectively, these processes contribute to chronic inflammation and genomic instability, which are key factors in the pathogenesis of H. pylori-related diseases, including gastritis and gastric cancer. Figure created with BioRender.com.