A number of human diseases are caused by inherited mitochondrial DNA mutations. Two of these diseases, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonic epilepsy and ragged-red fibres), are commonly caused by point mutations to tRNA genes encoded by mitochondrial DNA. Here we report on how these mutations affect mitochondrial function in primary fibroblast cultures established from a MELAS patient containing an A to G mutation at nucleotide 3243 in the tRNALeu(UUR) gene and a MERRF patient containing an A to G mutation at nucleotide 8344 in the tRNALys gene. Both mitochondrial membrane potential and respiration rate were significantly decreased in digitonin-permeabilized MELAS and MERRF fibroblasts respiring on glutamate/malate. A similar decrease in mitochondrial membrane potential was found in intact MELAS and MERRF fibroblasts. The mitochondrial content of these cells, estimated by stereological analysis of electron micrographs and from measurement of mitochondrial marker enzymes, was similar in control, MELAS and MERRF cells. Therefore, in cultured fibroblasts, mutation of mitochondrial tRNA genes leads to assembly of bioenergetically incompetent mitochondria, not to an alteration in their amount. However, the cell volume occupied by secondary lysosomes and residual bodies in the MELAS and MERRF cells was greater than in control cells, suggesting increased mitochondrial degradation in these cells. In addition, fibroblasts containing mitochondrial DNA mutations were 3–4-fold larger than control fibroblasts. The implications of these findings for the pathology of mitochondrial diseases are discussed.
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September 1996
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Research Article|
September 01 1996
Altered mitochondrial function in fibroblasts containing MELAS or MERRF mitochondrial DNA mutations
Andrew M JAMES;
Andrew M JAMES
*Department of Biochemistry, University of Otago, P.O. Box 56, Dunedin, New Zealand
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Yau-Huei WEI;
Yau-Huei WEI
†Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei, Taiwan 11221
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Cheng-Yoong PANG;
Cheng-Yoong PANG
†Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei, Taiwan 11221
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Michael P. MURPHY
Michael P. MURPHY
‡
*Department of Biochemistry, University of Otago, P.O. Box 56, Dunedin, New Zealand
‡To whom correspondence should be addressed.
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Publisher: Portland Press Ltd
Received:
November 30 1995
Revision Received:
May 02 1996
Accepted:
May 07 1996
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1996
1996
Biochem J (1996) 318 (2): 401–407.
Article history
Received:
November 30 1995
Revision Received:
May 02 1996
Accepted:
May 07 1996
Citation
Andrew M JAMES, Yau-Huei WEI, Cheng-Yoong PANG, Michael P. MURPHY; Altered mitochondrial function in fibroblasts containing MELAS or MERRF mitochondrial DNA mutations. Biochem J 1 September 1996; 318 (2): 401–407. doi: https://doi.org/10.1042/bj3180401
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