Mitochondrial deficiency in Cockayne syndrome

Abstract

Cockayne syndrome is a rare inherited disorder characterized by accelerated aging, cachectic dwarfism and many other features. Recent work has implicated mitochondrial dysfunction in the pathogenesis of this disease. This is particularly interesting since mitochondrial deficiencies are believed to be important in the aging process. In this review, we will discuss recent findings of mitochondrial pathology in Cockayne syndrome and suggest possible mechanisms for the mitochondrial dysfunction.

Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA

“…Using in silico and in vivo techniques, we find that transcription per se rather than downstream translational defects lead to mitochondrial pathology, a conclusion partly based on the discovery of mitochondrial dysfunction in the diseases hypomyelinating leukodystrophy 7 and spinocerebellar ataxia 17. Interestingly, the observed mitochondrial changes with increased mitochondrial membrane potential and oxygen consumption suggest that the changes are not caused by primary mitochondrial dysfunction but rather by a secondary compensatory response due to nuclear changes, as proposed previously (35,36). This is in agreement with a number of previous studies showing similar mitochondrial changes as a response to nuclear DNA damage whereas studies in nonisogenic cell lines in the context of Cockayne syndrome have been inconclusive (7,10,(37)(38)(39)(40)(41).…”

“…S2 E and F). Likewise, only modest changes in translation rates were seen by measuring incorporation of 35 S-labeled methionine and cysteine and by assessing polysome profiles in CSA-or CSB-deficient SH-SY5Y cells as well as in SH-SY5Y cells treated with transcriptional inhibitors (Fig. S2 G and H).…”

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

“…The PARP-sirtuin substrate competition has already been confirmed to impact SIRT1 downstream events linked to the regulation of cell death/survival [157] or mitochondrial metabolism [12]. Disruption of the SIRT1-PGC-1α axis by (over)activated PARP-1 has been suggested to be of significance for the pathomechanism of several DNA repair disorders accompanied by neurodegeneration where mitochondrial abnormalities may play significant roles [51,178,200]. SIRT1 inhibition via NAD + depletion might also mediate other neurodegenerative insults such as the death of hippocampal cells in culture in a model of acute epileptic neuron loss [212].…”

Cockayne syndrome pathogenesis: Lessons from mouse models

“…This is in line with an increasing amount of literature indicating that CS (but not XP cells) display increased vulnerability to inducers of oxidative DNA damage, and that CSB and CSA play a role in repair of oxidative DNA damage independent of the NER machinery Cramers et al, 2011;D'Errico et al, 2007;Melis et al, 2012;Nardo et al, 2009;Spivak and Hanawalt, 2006). CSB has been proposed to play a role in several oxidative DNA damage repair pathways, including transcription-coupled base excision repair, genome-wide base excision repair, and mitochondrial base excision repair, but additional repair unrelated mechanisms such as transcriptional bypass could play a role as well (Charlet-Berguerand et al, 2006;Cramers et al, 2011;Menoni et al, 2012;Nouspikel, 2008;Scheibye-Knudsen et al, 2013;Spivak and Hanawalt, 2006;Stevnsner et al, 2008). The increased vulnerability to ionizing radiation of Csb m/m versus Xpa À/À cells does not apply to embryonic stem cells, as Csb m/m and Xpa À/À embryonic stem cells display the same survival after exposure to gamma radiation.…”