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. May-Jun 2013;134(5-6):275-83.
doi: 10.1016/j.mad.2013.02.007. Epub 2013 Feb 19.

Mitochondrial Deficiency in Cockayne Syndrome

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Mitochondrial Deficiency in Cockayne Syndrome

Morten Scheibye-Knudsen et al. Mech Ageing Dev. .
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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 discuss recent findings of mitochondrial pathology in Cockayne syndrome and suggest possible mechanisms for the mitochondrial dysfunction.


Figure 1
Figure 1. Possible pathways to mitochondrial dysfunction in Cockayne syndrome
Defects in base excision DNA repair, the primary repair route for oxidative lesions, have been found in Cockayne syndrome (See figure 2). In addition mitochondrial transcription was shown recently to be decreased in Cockayne syndrome (See figure 3). Further defects in mitochondrial autophagy, mitophagy, has been found in Cockayne syndrome (See figure 4). Finally the mitochondrial dysfunction could stem from a nuclear defect (See figure 5).
Figure 2
Figure 2. Cockayne syndrome protein B regulates base excision repair
CSB has been shown to increase the incision activity of OGG1 and NEIL1; two glycosylases responsible for the initial step of removing oxidized lesions such as 8-oxo-G from the ribose backbone. This creates an abasic site that is recognized and removed by APE1 yielding a gab in the DNA strand. APE1 has been shown to physically and functionally interact with CSB. The resulting gap in the DNA is then further processed by short patch or long patch repair involving proteins such as DNA polymerase gamma, DNA ligase III, Fen1 and others.
Figure 3
Figure 3. Possible roles for CSB in mitochondrial transcription
CSB was recently shown to stimulate the RNA elongation activity of the mitochondrial polymerase. In this regard CSB could act either as a DNA annealing enzyme closing the transcription bubble after the RNA polymerase. Alternatively, CSB has been shown to be able to displace TFAM from the DNA strand. In this regard CSB could act to remove bound proteins from the DNA strand in front of the polymerase thereby facilitating transcription.
Figure 4
Figure 4. A possible role for CSB in mitophagy
CSB deficient cells were recently shown to be defective in mitophagy. In this regard CSB could act as a mitochondrial DNA damage sensor either directly or through currently unknown proteins inducing mitophagy through the mitochondrial permeability transition pore (mPTP) when an irreparable lesion is encountered. Ataxia telangiectasia mutated (ATM) protein could function in a similar fashion. OMM: outer mitochondrial membrane. IMM: Inner mitochondrial membrane.
Figure 5
Figure 5. Mitochondrial dysfunction secondary to a nuclear deficiency
Due to the unusual nature of the mitochondrial dysfunction in CSB with increased oxygen consumption, increased membrane potential and increased ROS production the phenotype could stem from a compensatory response to a nuclear defect. Here CSB acts through the canonical transcription coupled nucleotide DNA repair. A defect leads to increased PARP1 activation. Poly-ADP-ribosylation is an energetically demanding process leading to increased ATP consumption and thereby decreased ATP levels. To increase energy output from the mitochondria the cells decrease the amount of uncoupling proteins. This leads to increased membrane potential and consequently increased ROS formation that can further damage DNA leading to a vicious cycle.

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