Background and Purpose: Cereblon (CRBN) is an interacting protein with large-conductance calcium-activated potassium channels. A mutation of CRBN causes a mild type of mental retardation in humans. While, recent study suggested its novel function as AMPK inhibitor via direct interaction with AMPK a1 subunit. Disruption of CRBN gene enhanced hepatic AMPK activity and prevents high-fat diet induced obesity and insulin resistance in mice. The aim of study is to figure out the effect of CRBN KO in heart and its mitochondrial function.

Method and Results: Eight weeks of Control (CRBN^+/+) and CRBN KO (CRBN^-/-) models were examined their body weight, heart rate and heart/body ratio. In vivo cardiac functions of animals were assessed by echocardiography. To evaluate mitochondrial function of those animals, cardiac mitochondria of CRBN^+/+ and CRBN^-/- were isolated then examined their ATP contents and ATP production rate, ROS production rate, oxygen consumption rate (OCR) and membrane potential (ΔΨm).
As results, the body weight, heart weight and heart/body ration were not significantly different between CRBN^+/+ and CRBN^-/- mice. Echocardiography showed enhanced cardiac contractility in CRBN^-/- mice based on increased ejection fraction (%) and fractional shortening (%). In their mitochondria, basal ATP contents and substrate/ADP stimulated ATP production rate were significantly higher in CRBN^-/- mice than CRBN^+/+. In addition, basal H2O2 level and rotenone induced ROS production rates were significantly lower in CRBN^-/- mice than CRBN^+/+. CRBN KO mice showed higher single cell contractility with higher Ca²⁺ transient amplitude in isolated left ventricular cardiac myocytes.

Conclusion: Our results suggested that CRBN is an important mitochondrial functional regulator which link cytosol to mitochondrial energy metabolic signaling.

Keyword: Cereblon, cardiac contractility, mitochondrial energy metabolism.