Mitochondrial DNA mutations affect calcium handling in differentiated neurons

Trevelyan, Andrew, Kirby, Denise, Smulders-Srinivasan, Tora, Nooteboom, Marco, Acin-Perez, Rebecca, Enriquez, Jose, Whittington, Miles, Lightowlers, Robert and Turnbull, Doug (2010) Mitochondrial DNA mutations affect calcium handling in differentiated neurons. Brain, 133 (3). pp. 787-796. ISSN 0006-8950

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Abstract

Mutations in the mitochondrial genome are associated with a wide range of neurological symptoms, but many aspects of the basic neuronal pathology are not understood. One candidate mechanism, given the well-established role of mitochondria in calcium buffering, is a deficit in neuronal calcium homoeostasis. We therefore examined calcium responses in the neurons derived from various ‘cybrid’ embryonic stem cell lines carrying different mitochondrial DNA mutations. Brief (∼50 ms), focal glutamatergic stimuli induced a transient rise in intracellular calcium concentration, which was visualized by bulk loading the cells with the calcium dye, Oregon Green BAPTA-1. Calcium entered the neurons through N-methyl-D-aspartic acid and voltage-gated calcium channels, as has been described in many other neuronal classes. Intriguingly, while mitochondrial mutations did not affect the calcium transient in response to single glutamatergic stimuli, they did alter the responses to repeated stimuli, with each successive calcium transient decaying ever more slowly in mitochondrial mutant cell lines. A train of stimuli thus caused intracellular calcium in these cells to be significantly elevated for many tens of seconds. These results suggest that calcium-handling deficits are likely to contribute to the pathological phenotype seen in patients with mitochondrial DNA mutations.

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