Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation

Su, Kevin; Ma, Yina; Cacheux, Marine; Ilkan, Zeki; Raad, Nour; Muller, Grace K.; Wu, Xiaohong; Guerrera, Nicole; Thorn, Stephanie; Sinusas, Albert J.; Foretz, Marc; Viollet, Benoı̂t; Akar, Joseph G.; Akar, Fadi G.; Young, Lawrence H.

doi:10.1172/jci.insight.141213

Cited by 12 publications

(11 citation statements)

References 55 publications

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“…There is growing evidence linking AF to metabolic stress and inflammation (Gutierrez & Van Wagoner, 2015; Su et al ., 2022). In the cell, ribosomes control translation of proteins and their activity accounts for most of the cells energy consumption (Turi et al ., 2019).…”

Section: Discussionmentioning

confidence: 99%

“…in aged tissue) may be protective or a compensatory mechanism (Jung et al ., 2015). AMPK is a central regulator of energy homeostasis (Kim et al ., 2016) playing a key role in monitoring cellular energy metabolism and there is growing evidence around the importance of AMPK in the heart (Su et al ., 2022); (Dyck & Lopaschuk, 2006) (Arad et al ., 2007). Recently Cao et al (Cao et al ., 2017) showed that γ2-AMPK translocate into the nucleus to suppress pre-rRNA transcription and ribosome biosynthesis during stress, this reduces ER stress and cell death.…”

Section: Discussionmentioning

confidence: 99%

“…AMPK signalling is increased, and this consequently would be expected to affect ribosomal RNA transcription, as reflected in the genes that are upregulated (Supplementary File 1 Table 1) Su et al (2022) highlight a critical role played by AMPK signalling and the resultant alterations in electrophysiological function and structural remodelling in the atria. Additionally, Su et al (2022) highlight loss of AMPK affecting the expression of mRNA transcripts encoding gap junction proteins and ion channels in the atrium. Here, our goat model aligns with the notion of an upregulation of AMPK to downregulate energy-consuming processes like ribosome biogenesis.…”

Section: Identifying Differential Mrna Expression By Quantitative Tra...mentioning

confidence: 99%

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Compartmentalisation proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation

Ayagama

Charles

Bose

et al. 2023

Preprint

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Endolysosomes (EL) are known for their role in regulating both intracellular trafficking and proteostasis. EL help facilitate elimination of damaged membrane and cytosolic proteins, protein aggregates, membranous organelles and also play an important role in calcium signalling. Despite the importance of EL, their specific role in cardiovascular disease is not well understood. In particular, it's unclear how EL contribute to atrial pathology over longer time frames. To shed light on this question, we conducted a comprehensive analysis that involved proteomics, transcriptomics, integrated analysis, electron tomography, western blotting, and enzyme assays. To identify the role of EL in atrial fibrillation (AF), we applied a recently published organelle protein isolation method. We used this method to study biopsies from AF goat model and analyse the EL-specific proteins and pathways involved in this condition. Our results revealed the upregulation of the AMPK pathway and the expression of EL-specific proteins that were not found in whole tissue lysates (TL), including GAA, DYNLRB1, CLTB, SIRT3, CCT2, and muscle-specific HSPB2. We also observed structural anomalies, such as autophago-vacuole formation, irregularly shaped mitochondria, and glycogen deposition, which provide insights into the EL's contribution to AF and related pathways and molecular mechanisms. Overall, our findings suggest that EL play an important role in the development of AF over longer time frames, and provide a more detailed understanding of the underlying molecular processes involved.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Identifying Differential Mrna Expression By Quantitative Tra...mentioning

confidence: 99%

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Compartmentalisation proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation

Ayagama

Charles

Bose

et al. 2023

Preprint

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“…AMPK can be activated by metabolic stress and AF, and it plays a crucial role in preserving the integrity of atrial I Ca-L , Ca 2+ handling, and cell contractility. Reduced expression of AMPK in the atria resulted in alterations in electrophysiological properties and increased atrial ectopic activity prior to the onset of spontaneous AF [56] , [57] , [58] .…”

Section: Ferroptosis and Arrhymiasmentioning

confidence: 99%

The role of iron overload and ferroptosis in arrhythmia pathogenesis

Shen,

Fu,

Ding

et al. 2024

IJC Heart & Vasculature

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“…More than 33 million individuals are affected by AF, and the likelihood of having AF rises with age [ 3 , 4 ]. Electrophysiological and atrial remodeling alterations are believed to be the primary causes of the development of paroxysmal to persistent AF [ 5 ]. AF evolution is driven by atrial fibrosis, which is a hallmark of atrial structural remodeling [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Developing Pharmacological Therapies for Atrial Fibrillation Targeting Mitochondrial Dysfunction and Oxidative Stress: A Scoping Review

Menezes Júnior,

França-e-Silva,

Oliveira

et al. 2023

IJMS

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Atrial fibrillation (AF) is a cardiac arrhythmia caused by electrophysiological anomalies in the atrial tissue, tissue degradation, structural abnormalities, and comorbidities. A direct relationship exists between AF and altered mitochondrial activity resulting from membrane potential loss, contractile dysfunction, or decreased ATP levels. This review aimed to elucidate the role of mitochondrial oxidative mechanisms in AF pathophysiology, the impact of mitochondrial oxidative stress on AF initiation and perpetuation, and current therapies. This review followed the Preferred Reporting Items for Systematic Reviews and the Meta-Analysis Extension for Scoping Reviews. PubMed, Excerpta Medica Database, and Scopus were explored until June 2023 using “MESH terms”. Bibliographic references to relevant papers were also included. Oxidative stress is an imbalance that causes cellular damage from excessive oxidation, resulting in conditions such as AF. An imbalance in reactive oxygen species production and elimination can cause mitochondrial damage, cellular apoptosis, and cardiovascular diseases. Oxidative stress and inflammation are intrinsically linked, and inflammatory pathways are highly correlated with the occurrence of AF. AF is an intricate cardiac condition that requires innovative therapeutic approaches. The involvement of mitochondrial oxidative stress in the pathophysiology of AF introduces novel strategies for clinical treatment.

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Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation

Cited by 12 publications

References 55 publications

Compartmentalisation proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation

Compartmentalisation proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation

The role of iron overload and ferroptosis in arrhythmia pathogenesis

Developing Pharmacological Therapies for Atrial Fibrillation Targeting Mitochondrial Dysfunction and Oxidative Stress: A Scoping Review

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