Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging

Abstract

Defects in the DNA repair mechanism nucleotide excision repair (NER) may lead to tumors in xeroderma pigmentosum (XP) or to premature aging with loss of subcutaneous fat in Cockayne syndrome (CS). Mutations of mitochondrial (mt)DNA play a role in aging, but a link between the NER-associated CS proteins and base excision repair (BER)-associated proteins in mitochondrial aging remains enigmatic. We show functional increase of CSA and CSB inside mt and complex formation with mtDNA, mt human 8-oxoguanine glycosylase (mtOGG)-1, and mt single-stranded DNA binding protein (mtSSBP)-1 upon oxidative stress. MtDNA mutations are highly increased in cells from CS patients and in subcutaneous fat of aged Csbm/m and Csa−/− mice. Thus, the NER-proteins CSA and CSB localize to mt and directly interact with BER-associated human mitochondrial 8-oxoguanine glycosylase-1 to protect from aging- and stress-induced mtDNA mutations and apoptosis-mediated loss of subcutaneous fat, a hallmark of aging found in animal models, human progeroid syndromes like CS and in normal human aging.

Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy

“…Oxidative stress has been observed in several neurodegenerative diseases (Trushina and McMurray, 2007), providing a link between our findings of increased ROS production and decreased autophagy to the neuropathology seen in CS. These findings could also explain the accumulation of lesions found in mitochondria from CSB deficient cells (Muftuoglu et al, 2009;Osenbroch et al, 2009;Aamann et al, 2010;Kamenisch et al, 2010). The in creased oxygen and glucose consumption we observe indicates a state of cellular energy deprivation.…”

“…CSB localizes to the mitochondria and interacts with the nucle oid, especially under conditions of oxidative stress (Aamann et al, 2010;Kamenisch et al, 2010). We hypothesize that CSB plays a role as a sensor of mtDNA damage, either by directly binding to mtDNA or as an indirect signaling protein.…”

“…Endogenous oxidizing radicals originate pre dominantly from the mitochondria, where the mitochondrial BER machinery acts as the pri mary protector. Recent findings indicate that CSB is present in the mitochondria, suggesting a role for CSB in mitochondrial DNA (mtDNA) repair (Aamann et al, 2010;Kamenisch et al, 2010). We now report that CSB participates in mitochondrial maintenance by inducing…”

Dysmyelination not demyelination causes neurological symptoms in preweaned mice in a murine model of Cockayne syndrome

“…Suggestions have been made that CS caused by faulty responses to endogenously generated oxidative damage through additional deficiencies in base excision repair (18), mitochondrial activity (22), and coordination of a transcriptional response (4,23). However, although CSA and CSB patients have indistinguishable clinical disease, only CSB and not CSA or UV s cells are sensitive to oxidative damage (14,17,24).…”

Papel das proteínas XPD e DNA polimerase eta nas respostas de células humanas a danos no genoma

“…Além disso, recentemente foi descrita a presença de CSA e CSB na mitocôndria (Aamann et al, 2010;Kamenisch et al, 2010), onde essas proteínas parecem ser importantes no reparo do mtDNA, assim como na manutenção do estado redox das células (Pascucci et al, 2012). Dessa forma, ainda não há certeza sobre qual o mecanismo mais importante na patologia (principalmente neurológica) de CS, se são as deficiências no reparo ou na transcrição (Brooks, 2013), ou um mecanismo conjunto (Jaarsma et al, 2011); além disso, no caso da deficiência de reparo, também existe controvérsia sobre qual seria o tipo de dano responsável pela patologia neurológica (Cleaver et al, 2013).…”