Mitochondrial DNA in necrosis-like cell death in failing hearts: evidence and mechanisms fostering damage.

Abstract

Mitochondrial DNA (mtDNA) is increasingly recognized as a damage-associated molecular pattern (DAMP) that signals mitochondrial injury and the consequent prodeath molecular signature. Such mtDNA release triggers programmed necrotic pathways, specifically necroptosis and pyroptosis, both of which are central to the pathogenesis of heart failure (HF). Mechanically, mtDNA liberated from dysfunctional mitochondria engages cytosolic nucleic acid sensors and that it is associated with activation of necroptotic pathways via the Z-DNA binding protein 1 (ZBP1)-receptor-interacting protein kinase 3 (RIP3)-mixed lineage kinase domain-like pseudokinase (MLKL) axis. Similarly, it can stimulate cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling to promote the de novo synthesis of pro-necroptotic cytokines. Furthermore, the mtDNA release has been shown to promote pyroptosis through nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) and/or absent in melanoma 2 (AIM2) inflammasomes, amplifying a pro-inflammatory environment. The article examines the mechanistic crosstalk between these prodeath, pro-inflammatory pathways with a particular emphasis on how this mechanistic crosstalk drives HF. Consequently, it highlights circulating mtDNA as a key biomarker for HF severity. Lastly, it posits that mtDNA-targeted therapies, such as interventions preserving mitochondrial integrity and limiting mtDNA leakage and oxidation, as well as interventions inhibiting mtDNA-sensing pathways, may offer a viable strategy for novel therapeutic interventions in HF.