Disruption of mitochondria–sarcoplasmic reticulum microdomain connectomics contributes to sinus node dysfunction in heart failure

Abstract

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.

Mitochondrial Structure and Function in Human Heart Failure

“… 247 Mitofusin 2, a protein essential for MERC formation, 92 is reduced in HF in mice. 248 MERCs are composed of several proteins involved in the regulation of Ca 2+ homeostasis: GRP75 (glucose-regulated protein 75), a chaperone protein, acts as a crucial linker between the IP3Rs (inositol trisphosphate receptors) on the ER and the voltage-dependent anion channel (VDAC) 1 on the outer mitochondrial membrane. 234 , 235 In vitro studies have shown that IP3R3 is responsible for Orai-mediated Ca 2+ entry and store-operated Ca 2+ entry through the formation of a complex with STIM1 (stromal interaction molecule 1) following an inositol trisphosphate signaling cascade in low Ca 2+ conditions.…”

Mitochondria-associated endoplasmic reticulum membrane (MAM): a dark horse for diabetic cardiomyopathy treatment

“…The structural connection between the mitochondria and the ER is known as the mitochondria-associated ER membrane (MAM) [ 9 ]. Disruption of the MAM structure is a significant factor in the development of HF [ 10 ]. Single-cell transcriptional profiling demonstrates MAM-related proteins preferentially accumulate in cardiomyocytes during the initial stages of cardiac hypertrophy but gradually decrease as the disease progresses [ 11 ].…”

Arritmia sinusal: Caso clínico

“…La causa más común de esta patología es una lesión cerebral, provocada por el aumento de la presión intracraneal o hipoxia Teri M (2019). En los pacientes de la tercera edad que presentan esta patología pueden padecer algún tipo de cardiopatía Ren L et al (2022). Es una estructura fibrótica única, alargada, tridimensional ubicada en la unión de la región intercava de la vena cava superior que bordea la cresta terminal, se origina en el marcapasos intraganglionares y se conduce a las aurículas a través de una o más vías de conducción sino auricular discretas Kalyanasundaram et al (2023).…”