Bag3 Regulates Mitochondrial Function and the Inflammasome Through Canonical and Noncanonical Pathways in the Heart

Wang, JuFang; Tomar, Dhadendra; Martin, Thomas G.; Dubey, Shubham; Dubey, Praveen; Song, Jianliang; Landesberg, Gavin; McCormick, Michael G.; Myers, Valerie D.; Merali, Salim; Merali, Carmen; Lemster, Bonnie; McTiernan, Charles F.; Khalili, Kamel; Madesh, Muniswamy; Cheung, Joseph Y.; Kirk, Jonathan A.; Feldman, Arthur M.

doi:10.1016/j.jacbts.2022.12.013

Cited by 8 publications

(3 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is suggested that mitochondrial rRNA mutations can affect mitochondrial translation and can cause or modify the phenotype of cardiomyopathy(D. Li et al, 2019; S. Li et al, 2018; Santorelli et al, 1999). On the other hand, it is reported that BAG3 is essential for maintaining mitochondrial homeostasis, and changes in BAG3 expression have an adverse effect on cardiomyocyte function, which can shape the clinic of patient-5 with its mtDNA variants (Tahrir et al, 2017; Wang et al, 2023). A previously reported missense mutation in the MT-CO1 gene has been suggested to have a high likelihood of being associated with myopathy (Zaragoza et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Uncovering the Dual Role of Mitochondrial and Nuclear DNA Variants in Pediatric Cardiomyopathies

Temena,

Erzurumluoglu Gokalp,

Susam

et al. 2023

Preprint

View full text Add to dashboard Cite

Myocardial defects, originating from disruptions in genes affecting mitochondrial proteins interacting with others, have received limited research attention. In our study involving 27 pediatric cardiomyopathy patients, we explored mitochondrial and nuclear genes for four main cardiomyopathy subtypes. Sequencing cardiomyopathy-associated genes in patients was followed by whole mtDNA sequencing in these individuals, with 31 healthy pediatric controls for the latter part. Our findings uncovered significant pathogenic variants: MYH7 variants in three hypertrophic cardiomyopathy cases, a notable TNNC1 variant inherited interestingly in an autosomal recessive manner in two related restrictive cardiomyopathy patients, and a pathogenic TRDN variant in a left-ventricular non-compaction patient. Both a variant in FOXRED1, functioning in mitochondrial complex I stability, and a MT-CO1 variant were detected in two siblings, influencing early onset together. Additionally, a novel MT-RNR1 variant (m.684T>C) in one case might explain the phenotype. Our study highlights how both mtDNA and nDNA variants could have interconnected roles in understanding cardiomyopathy genetics. This study emphasizes that the functional studies are needed to recognize this dual relationship within bioenergetic pathways in cardiac muscle.

show abstract

Section: Discussionmentioning

confidence: 99%

Uncovering the Dual Role of Mitochondrial and Nuclear DNA Variants in Pediatric Cardiomyopathies

Temena,

Erzurumluoglu Gokalp,

Susam

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Deletion of bag3 gene in this case leads to cardiomyopathy both in dilated and restrictive forms (Myers et al, 2018). Work done by Feldman has shown that deletion of bag3 manifests in decrease in the enzymes of tricarboxylic acid pathway and of the MICU1 subunit of the Ca 2+ uniporter that are the onset signs of characteristics of heart failure (Wang et al, 2023a). Besides this, there is increasing body of research focussed on highlighting the importance of BAG3 mutations in predisposing to cardiac ailments (Domínguez et al, 2018).…”

Section: Role Of Bag3 In Various Diseases (Except Cancer)mentioning

confidence: 94%

Corelating the molecular structure of BAG3 to its oncogenic role

Pattoo,

Khanday

2024

Cell Biology International

View full text Add to dashboard Cite

BAG3 is a multifaceted protein characterised by having WW domain, PXXP motif and BAG domain. This protein gets upregulated during malignant transformation of cells and has been associated with poorer survival of patients. Procancerous activity of BAG domain of BAG3 is well documented. BAG domain interacts with ATPase domain of Hsp‐70 preventing protein delivery to proteasome. This impediment results in enhanced cell survival, proliferation, resistance to apoptosis and chemoresistance. Besides BAG domain other two domains/motifs of BAG3 are under research vigilance to explore its further oncogenic role. This review summarises the role of different structural determinants of BAG3 in elevating oncogenesis. Based on the already existing findings, more interacting partners of BAG3 are anticipated. The anticipated partners of BAG3 can shed a wealth of information into the mechanistic insights of its proproliferative role. Proper insights into the mechanistic details adopted by BAG3 to curtail/elaborate activity of anticipated interacting partners can serve as a potent target for development of therapeutic interventions.

show abstract

“…Luo et al, 2023), heart failure (HF) (J. Wang, Tomar, et al, 2023) and myocardial infraction (Fan et al, 2023). A variety of inflammasomes (NLRP3 [NOD-like receptor thermal protein domain associated protein 3], NLRP1, AIM2 [absent in melanoma 2] and NLRC4) have been linked to the development of cardiocerebrovascular diseases, and blocking these multiprotein complexes presents as a potential therapeutic target for disease regulation with only mild immunodeficiency side effects (Borborema et al, 2020;Deng et al, 2023;Shao et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

The cytoplasmic sensor, the AIM2 inflammasome: A precise therapeutic target in vascular and metabolic diseases

Lin,

Wang,

Fang

et al. 2024

British J Pharmacology

View full text Add to dashboard Cite

Cardio‐cerebrovascular diseases encompass pathological changes in the heart, brain and vascular system, which pose a great threat to health and well‐being worldwide. Moreover, metabolic diseases contribute to and exacerbate the impact of vascular diseases. Inflammation is a complex process that protects against noxious stimuli but is also dysregulated in numerous so‐called inflammatory diseases, one of which is atherosclerosis. Inflammation involves multiple organ systems and a complex cascade of molecular and cellular events. Numerous studies have shown that inflammation plays a vital role in cardio‐cerebrovascular diseases and metabolic diseases. The absent in melanoma 2 (AIM2) inflammasome detects and is subsequently activated by double‐stranded DNA in damaged cells and pathogens. With the assistance of the mature effector molecule caspase‐1, the AIM2 inflammasome performs crucial biological functions that underpin its involvement in cardio‐cerebrovascular diseases and related metabolic diseases: The production of interleukin‐1 beta (IL-1β), interleukin‐18 (IL-18) and N‐terminal pore‐forming Gasdermin D fragment (GSDMD‐N) mediates a series of inflammatory responses and programmed cell death (pyroptosis and PANoptosis). Currently, several agents have been reported to inhibit the activity of the AIM2 inflammasome and have the potential to be evaluated for use in clinical settings. In this review, we systemically elucidate the assembly, biological functions, regulation and mechanisms of the AIM2 inflammasome in cardio‐cerebrovascular diseases and related metabolic diseases and outline the inhibitory agents of the AIM2 inflammasome as potential therapeutic drugs.

show abstract

Bag3 Regulates Mitochondrial Function and the Inflammasome Through Canonical and Noncanonical Pathways in the Heart

Cited by 8 publications

References 69 publications

Uncovering the Dual Role of Mitochondrial and Nuclear DNA Variants in Pediatric Cardiomyopathies

Uncovering the Dual Role of Mitochondrial and Nuclear DNA Variants in Pediatric Cardiomyopathies

Corelating the molecular structure of BAG3 to its oncogenic role

The cytoplasmic sensor, the AIM2 inflammasome: A precise therapeutic target in vascular and metabolic diseases

Contact Info

Product

Resources

About