Aims: 

Mitochondrial cardiomyopathy is associated with deleterious remodeling of cardiomyocyte Ca²⁺ signalling partly due to suppressed expression of the sarcoplasmic reticulum (SR) Ca²⁺-buffer calsequestrin (CASQ2). This study aimed to determine if CASQ2 downregulation is directly caused by impaired mitochondrial function.

Methods and Results: 

Mitochondrial stress was induced in cultured neonatal rat cardiomyocytes by means of the mitochondrial uncoupler FCCP. Mitochondrial stress led to concentration-dependent downregulation of calsequestrin (CASQ2) expression, increased production of reactive oxygen species (ROS) and changes in the Ca²⁺ signals of the cardiomyocytes, accompanied by reduction in SR Ca²⁺ content and amplitude and duration of Ca²⁺ sparks. Caspase 3, p38 and p53 inhibitors had no effect on FCCP-induced CASQ2 downregulation; however, it was attenuated by the ROS scavenger N-acetylcysteine (NAC). Importantly, NAC not only decreased FCCP-induced ROS, but it also restored the Ca²⁺ signals, SR Ca²⁺ content and Ca²⁺ spark properties to control levels. Furthermore, CASQ2 promoter – luciferase construct and the endogenous CASQ2 gene responded similarly to mitochondrial uncoupling and NAC.

Conclusion: 

Mitochondrial uncoupling results in fast transcriptional changes in CASQ2 expression that manifest as compromised Ca²⁺ signalling, and these changes can be prevented by ROS scavengers. As impaired mitochondrial function has been implicated in several cardiac pathologies and well as in normal ageing, the mechanisms described here might be involved in a wide spectrum of cardiac conditions.