Findings reveal sex differences in mitochondrial calcium during ischemia, suggesting S-nitrosylation modifies cardiac injury response.
• Mitochondrial calcium accumulation during cardiac ischemia is sex-dependent. • Germline deletion of the mitochondrial Ca 2+ uniporter (MCU) eliminates sex differences. • S-Nitrosylation modulates MCU activity. • S-Nitrosylation of MCU is higher in female compared to male hearts. Mitochondrial calcium accumulation during cardiac ischemia is sex-dependent. Germline deletion of the mitochondrial Ca 2+ uniporter (MCU) eliminates sex differences. S-Nitrosylation modulates MCU activity. S-Nitrosylation of MCU is higher in female compared to male hearts. Sex differences in cardiac ischemia/reperfusion (I/R) injury have been reported, but the mechanisms underlying these differences remain poorly understood. As mitochondrial Ca 2+ accumulation plays an important role in I/R injury, we examined whether sex specific differences occur. To monitor mitochondrial Ca 2+ in Langendorf perfused hearts, we used a genetically encoded, mitochondrially targeted Ca 2+ indicator (R-GECO1) delivered via an adeno-associated viral vector (AAV9). Male hearts accumulated significantly more mitochondrial Ca 2+ during 20 min of ischemia than female hearts. Interestingly, sex differences in Ca 2+ accumulation during ischemia were not observed in hearts from mice lacking the mitochondrial Ca 2+ uniporter (MCU), suggesting an important role for MCU. As nitric oxide (NO) and its posttranslational modification S-nitrosylation have been suggested to modulate sex differences in Ca 2+ homeostasis, we inhibited NO signaling in female hearts, which increased mitochondrial Ca 2+ accumulation, while treatment of male hearts with an NO donor reduced mitochondrial Ca 2+ levels, indicating that S-nitrosylation modulates Ca 2+ uptake during ischemia in a sex-dependent manner. Using a biotin-switch assay in isolated mitochondria, we found increased S-nitrosylation of MCU in females compared to males. Finally, isolated male mitochondria exposed to an NO donor exhibited reduced Ca 2+ uptake, comparable to untreated female mitochondria. Taken together, these findings suggest that S-nitrosylation of MCU reduces mitochondrial Ca 2+ uptake during ischemia, uncovering a new layer of redox regulated mitochondrial function, with sex as a critical determinant.
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Barbara et al. (2026) studied this question.
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