Mitochondrial DNA: cellular genotoxic stress sentinel

Abstract

High copy number, damage prone, and lean on repair mechanisms are unique features of mitochondrial DNA (mtDNA) that are hard to reconcile with its essentiality for oxidative phosphorylation, the primary function ascribed to this maternally inherited component of our genome. We propose that mtDNA is also a genotoxic stress sentinel, as well as a direct second messenger of this type of cellular stress. Here, we discuss existing evidence for this sentinel/effector role through the ability of mtDNA to escape the confines of the mitochondrial matrix and activate nuclear DNA damage/repair responses via interferon-stimulated gene products and other downstream effectors. However, this arrangement may come at a cost, leading to cancer chemoresistance and contributing to inflammation, disease pathology, and aging.

Keywords: DNA repair; cGAS-STING; chemoresistance; interferon-stimulated gene (ISG); mtDNA; retrograde signaling.

Figure 1.. DNA-mediated innate immune and mtDNA-mediated genotoxic stress signaling.

(A) Upon DNA virus infection, the cellular DNA sensor cyclic GMP-AMP synthase (cGAS) (purple) binds the viral DNA and produces the small cyclic dinucleotide, 2′−3′-cyclic GMP-AMP (cGAMP) (small circle). Stimulator of interferon genes (STING) [shown at the endoplasmic reticulum (ER)] binds cGAMP and subsequently activates TBK1 (at the ER and Golgi intermediate compartment), resulting in the nuclear localization of IRF3, IRF7, and NF- B to activate transcription of type I interferon (IFN) and proinflammatory cytokines. Activation of type I IFN signaling leads to the formation of the ISGF3 transcription factor complex (green), composed of phosphorylated STAT1 (p-STAT1), phosphorylated STAT2 (p-STAT2), and IRF9 (see box below blue nucleus). ISGF3 induces expression of many IFN-stimulated genes (ISGs) as part of the antiviral response. (B) Similar to viral DNA, mtDNA released into the cytoplasm binds cGAS and activates STING and TBK1. However, in Tfam^+/– cells, where this pathway was unveiled, this instead leads to IRF3-dependent formation of the U-ISGF3 complex (composed of unphosphorylated STAT1, STAT2, and IRF9, see box below blue nucleus), which drives expression of a unique subset of ISGs (e.g., Parp9, Parp14, Isg15, Dtx3l, sp100, and Ifit1) that enhance nDNA repair. Other DNA repair-associated genes (e.g., Rtel1 and Pol ) are also upregulated in Tfam^+/– cells, that we propose, along with the DNA repair-associated ISGs, form an ‘mtDNA damage response regulon’ that enhances nDNA repair as part of the genotoxic stress sentinel function of mtDNA.