Nuclear DNA damage signalling to mitochondria in ageing

Abstract

Mitochondrial dysfunction is a hallmark of ageing, and mitochondrial maintenance may lead to increased healthspan. Emerging evidence suggests a crucial role for signalling from the nucleus to mitochondria (NM signalling) in regulating mitochondrial function and ageing. An important initiator of NM signalling is nuclear DNA damage, which accumulates with age and may contribute to the development of age-associated diseases. DNA damage-dependent NM signalling constitutes a network that includes nuclear sirtuins and controls genomic stability and mitochondrial integrity. Pharmacological modulation of NM signalling is a promising novel approach for the prevention and treatment of age-associated diseases.

Sirtuins: not only animal proteins

“…This protein is also involved in DNA damage repair. In neurons, it plays a role in DSBR (double-strand break Table 1 Localization and function for mammalian sirtuins Adapted from Shoba et al (2009), Houtkooper et al (2012 and Kupis et al (2016) AceCS2 acetyl-CoA synthetase 2, CPS1 carbamoyl phosphate synthetase 1, DNA Polb DNA polymerase b, FOXO forkhead box O, GABPb1 GA-binding protein b1, GDH glutamate dehydrogenase, HIF1a hypoxia-inducible factor 1a, NFjB nuclear factor-jB, PAR3 partitioning defective 3 homologue, PEPCK phosphoenolpyruvate carboxykinase, PGC1a peroxisome proliferator-activated receptor-c-co-activator, SOD2 superoxide dismutase 2, UCP-1 uncoupling protein 1, UOX urate oxidase repair) via NHEJ, while in proliferating cells, SIRT1 is involved in homologous recombination and base excision repair (BER) (Fang et al 2016). Yamamori et al (2010) proved that human AP endonucelase 1 (APE1) is a target for deacetylation by SIRT1, a protein that is directly involved in the repair of damaged DNA.…”

“…It increases chromatin-dependent repression of genes involved in epigenetic stabilization of ''oncogenic transformation''. It is assumed that SIRT7 may regulate mitochondrial homeostasis through deacetylation of GAbinding protein b1 (GABPb1) (Fang et al 2016). Tsai et al (2014) showed that SIRT7 are involved in ribosome biogenesis and protein synthesis.…”

NAD+ in DNA repair and mitochondrial maintenance

“…In 2 other DNA repair-deficient syndromes, Cockayne Syndrome (CS), 4,5 and Xeroderma Pigmentosum group A (XPA), 3 we reported that persistent nuclear DNA damage created a signal to mitochondria, which we called nuclear to mitochondrial (NM) signaling. 6 Nicotinamide adenine dinucleotide (NAD C ), an important metabolite in all human cells, was the signaling molecule. Emerging evidence strongly suggest NAD C is a key player in aging, neurodegeneration and metabolic diseases.…”

“…6 PARP1 is a major abundant nuclear protein, which serves as a sensor of DNA damage. In response to DNA damage, the rate of PAR synthesis increases rapidly up to 500-fold which can consume a significant amount of NAD C .…”

“…Ultimately, depletion of intracellular NAD C alters the NAD C / SIRT1 axis and leads to defects in mitochondrial homeostasis, ROS production, DNA repair and cell survival. 6 To test whether increased NAD C might ameliorate some of the features noted above we activate the NAD C /SIRT1 pathway using 3 strategies: NAD C supplementation with an NAD C precursor nicotinamide riboside (NR), PARP1 inhibition with olaparib or SIRT1 activation by SRT1720. Consistently, all 3 treatments improved the mitochondrial phenotypes, and decreased PARylation.…”