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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,9,6]]},"abstract":"<jats:p>\n                    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\n                    <jats:sup>2+<\/jats:sup>\n                    from the ryanodine receptors 2 (RyR2) on the sarcoplasmic reticulum (SR) at mitochondria\u2013SR microdomains serves as the critical communication to match energy production to meet metabolic demands. Therefore, we tested the hypothesis that alterations in the mitochondria\u2013SR connectomics contribute to SAN dysfunction in HF. We took advantage of a mouse model of chronic pressure overload\u2013induced HF by transverse aortic constriction (TAC) and a SAN-specific CRISPR-Cas9\u2013mediated knockdown of\n                    <jats:italic>mitofusin-2<\/jats:italic>\n                    (\n                    <jats:italic>Mfn2<\/jats:italic>\n                    ), the mitochondria\u2013SR 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\u2013SR distance. The expression of Mfn2 was significantly down-regulated and showed reduced colocalization with RyR2 in HF SAN cells. Indeed, SAN-specific\n                    <jats:italic>Mfn2<\/jats:italic>\n                    knockdown led to alterations in the mitochondria\u2013SR microdomains and SAN dysfunction. Finally, disruptions in the mitochondria\u2013SR microdomains resulted in abnormal mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    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\u2013SR microdomains in SAN automaticity and possible therapeutic targets for SAN dysfunction in HF patients.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2206708119","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T13:49:28Z","timestamp":1661953768000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":42,"title":["Disruption of mitochondria\u2013sarcoplasmic reticulum microdomain connectomics contributes to sinus node dysfunction in heart failure"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9731-8562","authenticated-orcid":false,"given":"Lu","family":"Ren","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, CA 95616"},{"name":"Stanford Cardiovascular Institute, Stanford University School 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