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Nuclear DNA damage signalling to mitochondria in ageing

Nature Reviews Molecular Cell Biology volume 17, pages 308–321 (2016)Cite this article

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Key Points

  • Mitochondrial dysfunction and genomic instability are two hallmarks of ageing.

  • Nuclear DNA damage accumulates with ageing and contributes to ageing-associated diseases. Signalling from the nucleus to mitochondria (NM signalling) has a crucial role in regulating mitochondrial function and ageing.

  • Three major NM signalling pathways link DNA damage to mitochondrial dysfunction: nuclear DNA repair and mitochondrial homeostasis; nuclear DNA damage-induced metabolic pathways; and regulation of mitophagy–apoptosis crosstalk by nuclear DNA repair-associated proteins.

  • NM signalling pathways can be targeted pharmacologically to promote healthy ageing and to treat age-associated diseases.

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.

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Figure 1: An overview of DNA damage-induced nucleus-to-mitochondria signalling and ageing.
Figure 2: PARP1–NAD+–SIRT1-mediated nuclear DNA damage to mitochondria signalling.
Figure 3: DNA damage-induced nucleus-to-mitochondria signalling is linked to metabolic dysfunction and age-associated diseases.
Figure 4: DNA damage signalling in the regulation of mitophagy and apoptosis.
Figure 5: Pharmacological interventions in the DNA damage response that may lead to increases in lifespan and healthspan.

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Change history

  • 24 March 2016

    The title of Figure 2 was incorrectly phrased in the original HTML and PDF versions of this article. This has been corrected to "PARP1–NAD+–SIRT1-mediated nuclear DNA damage to mitochondria signalling".

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Acknowledgements

The authors acknowledge the valuable work of the many investigators whose published articles they were unable to cite owing to space limitations. They thank Prabhat Khadka and Anne Tseng for critical reading of the manuscript. This research was supported entirely by the Intramural Research Program of the US National Institutes of Health (NIH) National Institute on Ageing (NIA). K.F.C. was supported by the Department of Veterans Affairs (Merit Award), research awards from the Glenn Foundation for Medical Research and the NIH/NIA (R56AG050997).

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  1. Evandro Fei Fang, Morten Scheibye-Knudsen and Vilhelm A. Bohr: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, 21224, Maryland, USA

    Evandro Fei Fang, Morten Scheibye-Knudsen, Deborah L. Croteau & Vilhelm A. Bohr

  2. Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, School of Medicine, Stanford University, Stanford, 94305, California, USA

    Katrin F. Chua

  3. Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, 94304, California, USA

    Katrin F. Chua

  4. Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, 21224, Maryland, USA

    Mark P. Mattson

  5. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Mark P. Mattson

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  1. Evandro Fei Fang
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Correspondence to Vilhelm A. Bohr.

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The Bohr laboratory has CRADA arrangements with ChromaDex and GlaxoSmithKline.

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DATABASES

Mito DB (The mitochondrial disease database)

Glossary

Cockayne syndrome

A rare accelerated-ageing disease with progressive neurodegeneration, caused by mutations in genes encoding two DNA repair proteins, CSA and CSB.

Xeroderma pigmentosum

A rare autosomal-recessive disorder characterized by severe sun sensitivity and skin cancer, associated with mutation of genes encoding a group of DNA repair proteins, XPA to XPG.

Ataxia telangiectasia

A genomic instability disease with progressive cerebellar neurodegeneration caused by mutation of the ataxia telangiectasia mutated (ATM) gene, encoding the kinase ATM, which is a master regulator of DNA damage processing.

Preiss–Handler pathway

A NAD+ biosynthetic process that consumes dietary nicotinic acid.

Salvage pathway

A NAD+ biosynthetic pathway that uses nicotinamide to generate nicotinamide mononucleotide (NMN), which is then transformed into NAD+.

Reactive oxygen species

(ROS). By-products of cellular metabolism, which at low levels provide health benefits, whereas at high levels they become increasingly noxious, with broad pathological consequences.

Ataxia telangiectasia mutated

(ATM). A 350 kDa Ser/Thr protein kinase that is required for activation of the DNA damage response to double-strand breaks through phosphorylation of >700 downstream DNA repair proteins.

Hepatosteatosis

Also known as hepatic steatosis (fatty liver). A common liver abnormality, in which patients have excessive accumulation of triglycerides (lipid droplets) in the liver.

Apurinic and apyrimidinic sites

(AP sites; also known as abasic sites). Sites of DNA sugar without a base, which is a common DNA lesion and is typically repaired by DNA base excision repair through sugar cleavage by AP endonuclease 1 (APE1).

8-oxo-dGuo

(8-oxo-7,8-dihydro-2′- deoxyguanosine). An oxidative DNA lesion, which can be repaired by DNA base excision repair.

NAD+/NADH ratio

NAD exists in cells in both oxidized (NAD+) and reduced (NADH) forms. The ratio of NAD+ and NADH regulates many cellular processes, including energy metabolism and mitochondrial functions.

Ketogenic diet

A diet that is high-fat, high-protein and low-carbohydrate.

Stress response

A cellular response to certain types of stress, such as caloric restriction or increase in reactive oxygen species, in which different stress-counteracting pathways are upregulated.

Autophagosome

A key structure of autophagy, an autophagosome is a spherical, double-membrane vesicle that sequesters cytoplasmic contents for degradation.

Rapamycin

A natural metabolite from the bacterium Streptomyces hygroscopicus, which inhibits mTOR and extends lifespan in species from yeast to fruit flies and mice.

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Fang, E., Scheibye-Knudsen, M., Chua, K. et al. Nuclear DNA damage signalling to mitochondria in ageing. Nat Rev Mol Cell Biol 17, 308–321 (2016). https://doi.org/10.1038/nrm.2016.14

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