Lysosomal Ca2+ flux modulates automaticity in ventricular cardiomyocytes and correlates with arrhythmic risk

An Xie; Gyeoung-Jin Kang; Eun Ji Kim; Feng Feng; Sophie E Givens; Brenda M Ogle; Samuel C Dudley Jr

doi:10.1093/pnasnexus/pgad174

Lysosomal Ca²⁺ flux modulates automaticity in ventricular cardiomyocytes and correlates with arrhythmic risk

PNAS Nexus. 2023 May 25;2(6):pgad174. doi: 10.1093/pnasnexus/pgad174. eCollection 2023 Jun.

Authors

An Xie^{1

2}, Gyeoung-Jin Kang^{1

2}, Eun Ji Kim^{1

2}, Feng Feng^{1

2}, Sophie E Givens³, Brenda M Ogle^{2

3

4}, Samuel C Dudley Jr^{1

2}

Affiliations

¹ Department of Medicine, University of Minnesota, 401 East River Parkway, VCRC 1st Floor, Suite 131, Minneapolis, MN 55455, USA.
² Lillehei Heart Institute, University of Minnesota, 2231 6th Street SE, Suite 4-156, Minneapolis, MN 55455, USA.
³ Department of Biomedical Engineering, Stem Cell Institute, University of Minnesota, McGuire Translational Research Facility, 2001 6th Street SE, Mail Code 2873, Minneapolis, MN 55455, USA.
⁴ Department of Pediatrics, Institute for Engineering in Medicine, University of Minnesota, 420 Delaware Street Southeast, 725 Mayo Memorial Building, MMC 94, Minneapolis, MN 55455, USA.

Abstract

Automaticity involves Ca²⁺ handling at the cell membrane and sarcoplasmic reticulum (SR). Abnormal or acquired automaticity is thought to initiate ventricular arrhythmias associated with myocardial ischemia. Ca²⁺ flux from mitochondria can influence automaticity, and lysosomes also release Ca²⁺. Therefore, we tested whether lysosomal Ca²⁺ flux could influence automaticity. We studied ventricular human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), hiPSC 3D engineered heart tissues (EHTs), and ventricular cardiomyocytes isolated from infarcted mice. Preventing lysosomal Ca²⁺ cycling reduced automaticity in hiPSC-CMs. Consistent with a lysosomal role in automaticity, activating the transient receptor potential mucolipin channel (TRPML1) enhanced automaticity, and two channel antagonists reduced spontaneous activity. Activation or inhibition of lysosomal transcription factor EB (TFEB) increased or decreased total lysosomes and automaticity, respectively. In adult ischemic cardiomyocytes and hiPSC 3D EHTs, reducing lysosomal Ca²⁺ release also inhibited automaticity. Finally, TRPML1 was up-regulated in cardiomyopathic patients with ventricular tachycardia (VT) compared with those without VT. In summary, lysosomal Ca²⁺ handling modulates abnormal automaticity, and reducing lysosomal Ca²⁺ release may be a clinical strategy for preventing ventricular arrhythmias.

Keywords: automaticity; calcium; cardiomyocytes; human-induced pluripotent stem cell; lysosome.

Grants and funding

R01 HL104025/HL/NHLBI NIH HHS/United States