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

Abstract

16Background: Cockayne syndrome (CS) is a rare premature aging disease, most 17 commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS 18 patients display cachectic dwarfism and severe neurological manifestations and have 19 an average life expectancy of 12 years. The CS proteins are involved in transcription 20 and DNA repair, with the latter including transcription-coupled nucleotide excision repair 21 (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, which 22 likely contributes to the severe premature aging phenotype of this disease. While 23 48 proteins. CSA [5, 6] and CSB [7] are DNA damage response proteins that are involved 49 in transcription-coupled nucleotide excision repair (TC-NER), as well as both nuclear 50 and mitochondrial base excision repair (BER) [8]. NER is a versatile DNA repair 51 pathway as it is responsible for the removal of a wide range of DNA adducts. CSA and 52 CSB are also important for transcription recovery after DNA damage [9][10][11]. Various 53 studies have shown that CSB plays a considerable role in transcription, and likely is a 54 transcription factor [12][13][14][15]. 55 56 Similar to other DNA repair-defective premature aging diseases, such as xeroderma 57 pigmentosum (XP) [16], ataxia-telangiectasia (AT) [17], and Werner syndrome (WS) 58[18], mitochondrial dysfunction is implicated in many CS phenotypes [3, 4, 19]. The 59 mechanisms of mitochondrial dysfunction underlying CS remain unclear but may involve 60 the impairment of the NAD + (nicotinamide adenine dinucleotide, oxidized)-mitophagy 61 axis [19][20][21][22]. NAD + is a fundamental molecule in cellular energy metabolism and 62 signaling pathways and is essential for adaptive responses of cells to bioenergetics and 63 oxidative stress; accordingly, there is an age-dependent depletion of cellular NAD + , 64 suggesting NAD + depletion as a major driver of both pathological and biological aging 65[23]. Many molecular mechanisms are involved in the multi-faceted effects of NAD + on 66 longevity and healthspan, including the induction of mitophagy, a cellular self-67 recognition, engulfment, degradation, and recycling of damaged and superfluous 68 mitochondria [24][25][26]. In CS, the accumulation of unrepaired DNA damage may lead to 69 to those observed in CS patients. After the selection of terms with p-values lower than 130 0.05 and an absolute value pathway Z-Score cut-off of 2.0, the remaining 39 GO terms 131and their respective Z-Scores were sorted by clustering in Fig 1b. Surprisingly, csa-1 132 and csb-1 worms had opposite pathway changes for a majority of the terms. Throughout 133 the dataset, csa-1;csb-1 worms partitioned more with csa-1 than csb-1 worms, 134suggesting that csa-1 drives the double mutant phenotype. However, there was a 135 shortlist of terms, including lysosome, where the csa-1;csb-1 worms segregated with 136 csb-1 worms. Other terms in this group included histidine catabolic process to glutamate 137 and formamide, oxidoreductase activity, an...

A C. elegans model for neurodegeneration in Cockayne syndrome

“…Further, we detect expansion of the mitochondrial mass and a hyperfused mitochondrial network, while respiratory activity is largely maintained. Our results on mitochondrial morphology changes are consistent with previous findings in C. elegans mutants for the csa-1 or csb-1 genes ( 53 ). Upon exogenous DNA damage, however, the mitochondria fragment and csb-1 mutants show a strong dampening of oxygen consumption indicative of mitochondrial dysfunction.…”

Long-term NAD+ supplementation prevents the progression of age-related hearing loss in mice

“…1b). One of the primary functions of NAD+ is to improve mitochondrial health by inducing mitochondrial turnover (14,15). To gain insight into the mechanism of action of NAD+'s benefit on hearing loss, we used WT (mtKeima) mice with a reporter gene to also assess mitochondrial degradation (mitophagy) in the cochlea (16).…”

Peripheral neuropathies associated with DNA repair disorders

“…61 In addition, the CS proteins also appear to play a role in the maintenance of mitochondrial homeostasis through NAD + signaling. 62,63 Among CS patients, 25% of cases result from pathogenic variants in CSA/ERCC8, whereas 75% of cases are caused by CSB/ERCC6. 58 In the setting of CSA or CSB deficiency, DNA damage remains unrepaired and RNA polymerase progression halts at lesion sites on the transcribed strand of active genes.…”

“…Other compelling data suggest that CSB is involved in the regulation of gene expression and that this (as opposed to deficient TC‐NER) may be the main cause of neurological dysfunction in CS 61 . In addition, the CS proteins also appear to play a role in the maintenance of mitochondrial homeostasis through NAD + signaling 62,63 …”