Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT.

BACKGROUND

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmic syndrome caused by mutations in the calcium (Ca) release channel ryanodine receptor (RyR2) and its accessory proteins. These mutations make the channel leaky, resulting in Ca-dependent arrhythmias. Besides arrhythmias, CPVT hearts typically lack structural cardiac remodeling, a characteristic often observed in other cardiac conditions (heart failure, prediabetes) also marked by RyR2 leak. Recent studies suggest that mitochondria are able to accommodate more Ca influx to inhibit arrhythmias in CPVT. Thus, we hypothesize that CPVT mitochondria can absorb diastolic Ca to protect the heart from cardiac remodeling.

METHODS AND RESULTS

The Mitochondrial Ca uniporter (MCU), the main mitochondrial Ca uptake protein, was conditionally knocked out in a CPVT model of calsequestrin 2 (CASQ2) KO. In vivo cardiac function was impaired in the CASQ2-MCU model as assessed by echocardiography. Cardiac dilation and cellular hypertrophy were also observed in the CASQ2-MCU hearts. Live-cell imaging identified altered Ca handling and increased oxidative stress in CASQ2-MCU myocytes. The activation status of Ca-dependent remodeling pathways (CaMKII, Calcineurin) was not altered in the CASQ2-MCU model. RNAseq identified changes in the transcriptome of the CASQ2-MCU hearts, distinct from the classic cardiac remodeling program of fetal gene re-expression.

CONCLUSIONS

We present genetic evidence that mitochondria play a protective role in CPVT. MCU-dependent Ca uptake is crucial for preventing pathological cardiac remodeling in CPVT.