期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：36
DOI：10.1073/pnas.2206708119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The human heart beats 60 to 80 times a minute, which can amount to more than 3 billion heartbeats in one’s lifetime. Each heartbeat is initiated by the sinoatrial node (SAN). SAN dysfunction is a common feature of heart failure (HF). However, the underlying mechanisms are not entirely understood. Here, we demonstrate that disruptions in mitochondria–sarcoplasmic reticulum (SR) connectomics contribute, at least in part, to SAN dysfunction in HF. Electron microscope tomography reveals abnormal mitochondrial structure with increased mitochondria–SR distance. In HF SAN cells, the mitochondria–SR tethering GTPase protein, mitofusin-2 (Mfn2), is significantly down-regulated. Furthermore, SAN-specific
Mfn2 knockdown results in SAN dysfunction. The findings highlight the roles of mitochondria–SR connectomics in SAN dysfunction commonly seen with HF.
The sinoatrial node (SAN), the leading pacemaker region, generates electrical impulses that propagate throughout the heart. SAN dysfunction with bradyarrhythmia is well documented in heart failure (HF). However, the underlying mechanisms are not completely understood. Mitochondria are critical to cellular processes that determine the life or death of the cell. The release of Ca
2+ from the ryanodine receptors 2 (RyR2) on the sarcoplasmic reticulum (SR) at mitochondria–SR microdomains serves as the critical communication to match energy production to meet metabolic demands. Therefore, we tested the hypothesis that alterations in the mitochondria–SR connectomics contribute to SAN dysfunction in HF. We took advantage of a mouse model of chronic pressure overload–induced HF by transverse aortic constriction (TAC) and a SAN-specific CRISPR-Cas9–mediated knockdown of
mitofusin-2 (
Mfn2), the mitochondria–SR tethering GTPase protein. TAC mice exhibited impaired cardiac function with HF, cardiac fibrosis, and profound SAN dysfunction. Ultrastructural imaging using electron microscope (EM) tomography revealed abnormal mitochondrial structure with increased mitochondria–SR distance. The expression of Mfn2 was significantly down-regulated and showed reduced colocalization with RyR2 in HF SAN cells. Indeed, SAN-specific
Mfn2 knockdown led to alterations in the mitochondria–SR microdomains and SAN dysfunction. Finally, disruptions in the mitochondria–SR microdomains resulted in abnormal mitochondrial Ca
2+ handling, alterations in localized protein kinase A (PKA) activity, and impaired mitochondrial function in HF SAN cells. The current study provides insights into the role of mitochondria–SR microdomains in SAN automaticity and possible therapeutic targets for SAN dysfunction in HF patients.
