MERRF (myoclonus epilepsy associated with ragged-red fibres) is a maternally inherited mitochondrial encephalomyopathy with various syndromes involving both muscular and nervous systems. The most common mutation in MERRF syndrome, the A8344G mutation in mtDNA, has been associated with severe defects in the respiratory function of mitochondria. In the present study, we show that there is a significant decrease in CA8 (carbonic anhydrase-related protein VIII) in cybrids harbouring the MERRF A8344G mutation. CA8 deficiency and mutations were found to be associated with a distinctive lifelong gait disorder in wdl (Waddles) mice and novel syndromes characterized by cerebellar ataxia and mental retardation in humans. The results of the present study showed that overexpression of CA8 in MERRF cybrids significantly decreased cell death induced by STS (staurosporine) treatment, suggesting a protective function of CA8 in cells harbouring the A8344G mutation of mtDNA. Interestingly, an increase in the formation of LC3-II (microtubule-associated protein 1 light chain 3-II) was found in the cybrids with down-regulated CA8 expression, suggesting that reduced expression of CA8 leads to autophagy activation. Furthermore, cybrids exhibiting down-regulated CA8 showed increased cytosolic Ca2+ signals and reduced levels of phospho-Akt compared with those in the cybrids with overexpressed CA8, indicating that phospho-Akt is involved in the protection of cells by CA8. Our findings suggest that CA8 is involved in the autophagic pathway and may have a protective role in cultured cells from patients with MERRF. Targeting CA8 and the downstream autophagic pathway might help develop therapeutic agents for treatment of MERRF syndrome in the future.
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Research Article|
March 14 2014
Effects of carbonic anhydrase-related protein VIII on human cells harbouring an A8344G mitochondrial DNA mutation
Tze-Kai Wang;
Tze-Kai Wang
*Department of Life Science, Tunghai University, Taichung, Taiwan, Republic of China
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Che-Kun Cheng;
Che-Kun Cheng
*Department of Life Science, Tunghai University, Taichung, Taiwan, Republic of China
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Tang-Hao Chi;
Tang-Hao Chi
*Department of Life Science, Tunghai University, Taichung, Taiwan, Republic of China
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Yi-Shing Ma;
Yi-Shing Ma
†Department of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan, Republic of China
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Shi-Bei Wu;
Shi-Bei Wu
†Department of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan, Republic of China
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Yau-Huei Wei;
Yau-Huei Wei
†Department of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan, Republic of China
‡Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, Republic of China
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Mingli Hsieh
Mingli Hsieh
1
*Department of Life Science, Tunghai University, Taichung, Taiwan, Republic of China
§Life Science Research Center, Tunghai University, Taichung, Taiwan, Republic of China
1To whom correspondence should be addressed (email mhsieh@thu.edu.tw).
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Publisher: Portland Press Ltd
Received:
September 17 2013
Revision Received:
January 28 2014
Accepted:
January 30 2014
Accepted Manuscript online:
January 30 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 459 (1): 149–160.
Article history
Received:
September 17 2013
Revision Received:
January 28 2014
Accepted:
January 30 2014
Accepted Manuscript online:
January 30 2014
Citation
Tze-Kai Wang, Che-Kun Cheng, Tang-Hao Chi, Yi-Shing Ma, Shi-Bei Wu, Yau-Huei Wei, Mingli Hsieh; Effects of carbonic anhydrase-related protein VIII on human cells harbouring an A8344G mitochondrial DNA mutation. Biochem J 1 April 2014; 459 (1): 149–160. doi: https://doi.org/10.1042/BJ20131235
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