Bradley S. Launikonis

Aim A fraction of the Ca 2+ released from the sarcoplasmic reticulum (SR) enters mitochondria to transiently increase its [Ca 2+ ] ([Ca 2+ ] mito ). This transient [Ca 2+ ] mito increase may be important in the resynthesis of ATP and other processes. The resynthesis of ATP in the mitochondria generates heat that can lead to hypermetabolic reactions in muscle with ryanodine receptor 1 (RyR1) variants during the cyclic releasing of SR Ca 2+ in the presence of a RyR1 agonist. We aimed to analyse whether the mitochondria of RYR1 variant muscle handles Ca 2+ differently from healthy muscle. Methods We used confocal microscopy to track mitochondrial and cytoplasmic Ca 2+ with fluorescent dyes simultaneously during caffeine‐induced Ca 2+ waves in extensor digitorum longus muscle fibres from healthy mice and mice heterozygous (HET) for a malignant hyperthermia‐causative RYR1 variant. Results Mitochondrial Ca 2+ ‐transient peaks trailed the peak of cytoplasmic Ca 2+ transients by many seconds with [Ca 2+ ] mito not increasing by more than 250 nM. A strong linear relationship between cytoplasmic Ca 2+ and [Ca 2+ ] mito amplitudes was observed in HET RYR1 KI fibres but not wild type (WT). Conclusion Our results indicate that [Ca 2+ ] mito change within the nM range during SR Ca 2+ release. HET fibre mitochondria are more sensitive to SR Ca 2+ release flux than WT. This may indicate post‐translation modification differences of the mitochondrial Ca 2+ uniporter between the genotypes.