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Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling

Okur, Mustafa N. ; Fang, Evandro F. ; Fivenson, Elayne M. ; Tiwari, Vinod ; Croteau, Deborah L. ; Bohr, Vilhelm A.

Aging cell, 2020-12, Vol.19 (12), p.e13268-n/a [Revista revisada por pares]

England: John Wiley & Sons, Inc

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Título:
Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling
Autor: Okur, Mustafa N. ; Fang, Evandro F. ; Fivenson, Elayne M. ; Tiwari, Vinod ; Croteau, Deborah L. ; Bohr, Vilhelm A.
Materias: accelerated ageing ; Aging ; AMPK ; Animal models ; Autophagy ; Biosynthesis ; Cerebellum ; Cockayne syndrome ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA repair ; Dwarfism ; Fatty acids ; Gene expression ; Genetic aspects ; Genetic transcription ; Homeostasis ; Life span ; Metabolism ; Mitochondria ; Mitochondrial DNA ; mitochondrial maintenance ; mitophagy ; Mutation ; NAD ; Nematodes ; Neurophysiology ; Nucleotide excision repair ; Original ; Original Paper ; Oxidative stress ; Patients ; Phagocytosis ; Phenotypes ; Proteins ; Supplements ; Transcription
Es parte de: Aging cell, 2020-12, Vol.19 (12), p.e13268-n/a
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Okur and Fang contributed equally.
Descripción: Cockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12 years. The CS proteins are involved in transcription and DNA repair, with the latter including transcription‐coupled nucleotide excision repair (TC‐NER). However, there is also evidence for mitochondrial dysfunction in CS, which likely contributes to the severe premature aging phenotype of this disease. While damaged mitochondria and impaired mitophagy were characterized in mice with CSB deficiency, such changes in the CS nematode model and CS patients are not fully known. Our cross‐species transcriptomic analysis in CS postmortem brain tissue, CS mouse, and nematode models shows that mitochondrial dysfunction is indeed a common feature in CS. Restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the CS nematodes, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. In cerebellar samples from CS patients, we found molecular signatures of dysfunctional mitochondrial dynamics and impaired mitophagy/autophagy. In primary cells depleted for CSA or CSB, this dysfunction can be corrected with supplementation of NAD+ precursors. Our study provides support for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy/autophagy. Together, these three agents contribute to an accelerated aging program that can be averted by cellular NAD+ restoration. Cross‐species analysis in CS postmortem brain tissue, CS cell, mouse, and nematode models indicates that mitochondrial dysfunction is a common feature in CS. Augmenting NAD+ levels by supplementing NAD+ precursors such as NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide) in CS can ameliorate age‐associated defects and mitochondrial abnormalities.
Editor: England: John Wiley & Sons, Inc
Idioma: Inglés;Noruego

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Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling

Okur, Mustafa N. ; Fang, Evandro F. ; Fivenson, Elayne M. ; Tiwari, Vinod ; Croteau, Deborah L. ; Bohr, Vilhelm A.

England: John Wiley & Sons, Inc

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