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

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmic syndrome caused by mutations in the calcium (Ca²⁺) release channel ryanodine receptor (RyR2) and its accessory proteins. These mutations make the channel leaky, resulting in Ca²⁺-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 Ca²⁺ influx to inhibit arrhythmias in CPVT. Thus, we hypothesize that CPVT mitochondria can absorb diastolic Ca²⁺ to protect the heart from cardiac remodeling.

The Mitochondrial Ca²⁺ uniporter (MCU), the main mitochondrial Ca²⁺ 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^CKO model as assessed by echocardiography. Cardiac dilation and cellular hypertrophy were also observed in the CASQ2^-/--MCU^CKO hearts. Live-cell imaging identified altered Ca²⁺ handling and increased oxidative stress in CASQ2^-/--MCU^CKO myocytes. The activation status of Ca²⁺-dependent remodeling pathways (CaMKII, Calcineurin) was not altered in the CASQ2^-/--MCU^CKO model. RNAseq identified changes in the transcriptome of the CASQ2^-/--MCU^CKO hearts, distinct from the classic cardiac remodeling program of fetal gene re-expression.

We present genetic evidence that mitochondria play a protective role in CPVT. MCU-dependent Ca²⁺ uptake is crucial for preventing pathological cardiac remodeling in CPVT.