Journal Article

Increased mitochondrial Ca<sup>2+</sup> and decreased sarcoplasmic reticulum Ca<sup>2+</sup> in mitochondrial myopathy

Jan Aydin, Daniel C. Andersson, Sandra L. Hänninen, Anna Wredenberg, Pasi Tavi, Chan Bae Park, Nils-Göran Larsson, Joseph D. Bruton and Håkan Westerblad

in Human Molecular Genetics

Volume 18, issue 2, pages 278-288
Published in print January 2009 | ISSN: 0964-6906
Published online October 2008 | e-ISSN: 1460-2083 | DOI:
Increased mitochondrial Ca2+ and decreased sarcoplasmic reticulum Ca2+ in mitochondrial myopathy

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Genetic mutations that affect mitochondrial function often cause skeletal muscle dysfunction. Here, we used mice with skeletal-muscle-specific disruption of the nuclear gene for mitochondrial transcription factor A (Tfam) to study whether changes in cellular Ca2+ handling is part of the mechanism of muscle dysfunction in mitochondrial myopathy. Force measurements were combined with measurements of cytosolic Ca2+, mitochondrial Ca2+ and membrane potential and reactive oxygen species in intact, adult muscle fibres. The results show reduced sarcoplasmic reticulum (SR) Ca2+ storage capacity in Tfam KO muscles due to a decreased expression of calsequestrin-1. This resulted in decreased SR Ca2+ release during contraction and hence lower force production in Tfam KO than in control muscles. Additionally, there were no signs of oxidative stress in Tfam KO cells, whereas they displayed increased mitochondrial [Ca2+] during repeated contractions. Mitochondrial [Ca2+] remained elevated long after the end of stimulation in muscle cells from terminally ill Tfam KO mice, and the increase was smaller in the presence of the cyclophilin D-binding inhibitor cyclosporin A. The mitochondrial membrane potential in Tfam KO cells did not decrease during repeated contractions. In conclusion, we suggest that the observed changes in Ca2+ handling are adaptive responses with long-term detrimental effects. Reduced SR Ca2+ release likely decreases ATP expenditure, but it also induces muscle weakness. Increased [Ca2+]mit will stimulate mitochondrial metabolism acutely but may also trigger cell damage.

Journal Article.  7940 words.  Illustrated.

Subjects: Genetics and Genomics

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