Mitochondrial DNA stress signalling protects the nuclear genome

Abstract

The mammalian genome comprises nuclear DNA (nDNA) derived from both parents and mitochondrial DNA (mtDNA) that is maternally inherited and encodes essential proteins required for oxidative phosphorylation. Thousands of copies of the circular mtDNA are present in most cell types that are packaged by TFAM into higher-order structures called nucleoids1. Mitochondria are also platforms for antiviral signalling2 and, due to their bacterial origin, mtDNA and other mitochondrial components trigger innate immune responses and inflammatory pathology 2,3 . We showed previously that instability and cytoplasmic release of mtDNA activates the cGAS-STING-Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Temporal Telomere and DNA Damage Responses in the Space Radiation Environment

“…Persistent mitochondrial stress during spaceflight (da Silveira, 2020; Bezdan, 2020) likely occurs in response to chronic exposure to the space radiation environment and the associated DNA damage; mtDNA has been shown to trigger innate immune responses and inflammation, which was also significantly elevated during spaceflight in the three crewmembers reported here ( Figure S4). Furthermore, mtDNA has recently been proposed as a stress sentinel, eliciting a protective signaling response that enhances nuclear DNA repair (Wu et al, 2019), a view also consistent with findings reported in the Twins Study (Garrett-Bakelman et al, 2019). The findings of increased mtDNA and mitochondrial RNA (mtRNA) during spaceflight are supportive of increased mitochondrial biogenesis, and potentially related telomere elongation, as a positive correlation between mtDNA copy number and telomere length in healthy adults has been demonstrated previously (Tyrka et al, 2015).…”

The cGAS–STING pathway as a therapeutic target in inflammatory diseases

“…Among the best studied examples, is that defective packaging of mtDNA into nucleoids following the depletion of transcription factor A mitochondrial (TFAM) is a prominent signal for cGAS activity in diverse cells 87 . In addition, mtDNA stress invoked by lack of mitochondrial endonuclease G or by treatment with chemotherapeutic drugs activates cells via cGAS 92 , 93 . In these and other instances, mtDNA may also be modified by mitochondrial reactive oxygen species that can render mtDNAs more resistant to processing by the nuclease TREX1 and hence more stimulatory 94 .…”

A New Twist in Protein Kinase B/Akt Signaling: Role of Altered Cancer Cell Metabolism in Akt-Mediated Therapy Resistance

“…Among those, especially metformin, rotenone, malonate, atovaquone, hydrocortisone and oligomycin are promising examples (for a more detailed discussion see [ 227 , 228 ]). However, the most interesting target in the TCA cycle is IDH1/2: IDH1/2 is frequently mutated in aggressive cancers and contributes to various aspects of malignant growth, including also epigenetic regulation of DSB repair [ 22 , 230 ]. Drugs targeting both IDH isoforms have already been approved for cancer treatment [ 231 , 232 ].…”