Mitochondrial calcium depletion in Darier disease is rescued by dantrolene sodium partly via MCU.

Darier disease (DD), caused by ATP2A2 mutations, disrupts epidermal adhesion via endoplasmic reticulum (ER) calcium defects. While ER calcium depletion is documented, its impact on mitochondrial calcium homeostasis remains unknown. This study investigates mitochondrial calcium downregulation in DD and evaluates repurposing the ryanodine receptor (RyR) antagonist dantrolene to restore mitochondrial function. Using primary, immortalised DD and ATP2A2 knockout keratinocytes as well as patient fibroblasts, we measured mitochondrial morphology and calcium level. DD models showed fragmented mitochondria and diminished respiratory function. These changes were associated with significantly lower mitochondrial calcium in keratinocytes. Dantrolene increased mitochondrial calcium uptake, partly via the mitochondrial calcium uniporter (MCU), enhancing TCA cycle enzyme activity and improving mitochondrial respiration. This recovery strengthened cell-cell adhesion in DD keratinocytes. Mitochondrial calcium reduction is a critical mediator in DD. Dantrolene ameliorates this calcium dyshomeostasis and disease phenotypes, proposing a therapeutic strategy using an FDA-approved drug.