Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling

Gambardella, Jessica; Jankauskas, Stanislovas S.; Kansakar, Urna; Varzideh, Fahimeh; Avvisato, Roberta; Prevete, Nella; Mone, Pasquale; Wang, Xujun; Lombardi, Angela; Santulli, Gaetano

doi:10.1016/j.jacbts.2023.03.014

Cited by 17 publications

(6 citation statements)

References 30 publications

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“…A mounting body of evidence supports a future for 'clinical epigenetics' in cardiovascular medicine. [22][23][24][25][26]28,29 Specifically, AF multiomic analysis on atrial tissues has provided novel into the molecular pathways implicated in the pathology. 4,32,50,51 However, the need of cardiac biopsies, has limited enthusiasm of this technology to a small subpopulation of AF including those with valvular heart disease or CHD, for whom surgical intervention is already warranted.…”

Section: Discussionmentioning

confidence: 99%

“…[22][23][24][25][26][27] DNA methylation levels resulted significantly increased in failing heart derived cardiomyocytes where correlate with functional and structural cardiac parameters, 28 as well as maladaptive chromatin remodelling emerged as a key mechanism in post ischemic heart injury. 29 In addition, in the myocardial tissue AF patients was found both an aberrant global DNA methylation 8,30 and specific epigenetic dysregulations in genes involved in inflammation, sodium and potassium ion transport, fibrosis, transcription regulation as well as in noncoding regions. 4,7,[30][31][32][33][34] Although preliminary studies of DNA isolated from blood confer some predictive efficacy in post-operative AF, 35 no evidence currently links circulatory and/or immunologic changes in the epigenome to AF.…”

Section: Introductionmentioning

confidence: 99%

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CDK5R1,GSE1,HSPG2andWDFY3as indirect epigenetic‐sensitive genes in atrial fibrillation

Infante,

Pepin,

Ruocco

et al. 2023

Eur J Clin Investigation

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BackgroundAlthough mounting evidence supports that aberrant DNA methylation occurs in the hearts of patients with atrial fibrillation (AF), noninvasive epigenetic characterization of AF has not yet been defined.MethodsWe investigated DNA methylome changes in peripheral blood CD4+ T cells isolated from 10 patients with AF relative to 11 healthy subjects (HS) who were enrolled in the DIANA clinical trial (NCT04371809) via reduced‐representation bisulfite sequencing (RRBS).ResultsAn atrial‐specific PPI network revealed 18 hub differentially methylated genes (DMGs), wherein ROC curve analysis revealed reasonable diagnostic performance of DNA methylation levels found within CDK5R1 (AUC = 0.76; p = 0.049), HSPG2 (AUC = 0.77; p = 0.038), WDFY3 (AUC = 0.78; p = 0.029), USP49 (AUC = 0.76; p = 0.049), GSE1 (AUC = 0.76; p = 0.049), AIFM1 (AUC = 0.76; p = 0.041), CDK5RAP2 (AUC = 0.81; p = 0.017), COL4A1 (AUC = 0.86; p < 0.001), SEPT8 (AUC = 0.90; p < 0.001), PFDN1 (AUC = 0.90; p < 0.01) and ACOT7 (AUC = 0.78; p = 0.032). Transcriptional profiling of the hub DMGs provided a significant overexpression of PSDM6 (p = 0.004), TFRC (p = 0.01), CDK5R1 (p < 0.001), HSPG2 (p = 0.01), WDFY3 (p < 0.001), USP49 (p = 0.004) and GSE1 (p = 0.021) in AF patients vs HS.ConclusionsCDK5R1, GSE1, HSPG2 and WDFY3 resulted the best discriminatory genes both at methylation and gene expression level. Our results provide several candidate diagnostic biomarkers with the potential to advance precision medicine in AF.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CDK5R1,GSE1,HSPG2andWDFY3as indirect epigenetic‐sensitive genes in atrial fibrillation

Infante,

Pepin,

Ruocco

et al. 2023

Eur J Clin Investigation

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“…BHB can also enhance mitochondrial respiration by mediating cytosolic calcium signaling [201]. Gambardella unveiled that BHB treatment on ischemic cardiomyocytes improved the transcription repression of PGC1α by reducing epigenetic modification induced by ischemia [202]. Gómora-García also employed cultured neurons and concluded that BHB, by targeting SIRT2, can promote mitophagy and increase mitochondrial biogenesis via PGC1α [203].…”

Section: Amino Acid and α-Kg Metabolismmentioning

confidence: 99%

Mitochondrial Dysfunction: A Roadmap for Understanding and Tackling Cardiovascular Aging

Zhang,

Muhetarijiang,

Chen

et al. 2024

Aging and disease

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Cardiovascular aging is a progressive remodeling process constituting a variety of cellular and molecular alterations that are closely linked to mitochondrial dysfunction. Therefore, gaining a deeper understanding of the changes in mitochondrial function during cardiovascular aging is crucial for preventing cardiovascular diseases. Cardiac aging is accompanied by fibrosis, cardiomyocyte hypertrophy, metabolic changes, and infiltration of immune cells, collectively contributing to the overall remodeling of the heart. Similarly, during vascular aging, there is a profound remodeling of blood vessel structure. These remodeling present damage to endothelial cells, increased vascular stiffness, impaired formation of new blood vessels (angiogenesis), the development of arteriosclerosis, and chronic vascular inflammation. This review underscores the role of mitochondrial dysfunction in cardiac aging, exploring its impact on fibrosis and myocardial alterations, metabolic remodeling, immune response remodeling, as well as in vascular aging in the heart. Additionally, we emphasize the significance of mitochondria-targeted therapies in preventing cardiovascular diseases in the elderly.

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“…Proper substrate utilization is imperative for the myocardium to fulfill its function, primarily relying on ATP (re-)synthesis through fatty acid oxidation within mitochondria [51] . The myocyte employs additional pathways, such as glycolysis, creatine kinase, and adenylate kinase, in response to high ATP demand.…”

Section: Mitochondrial Dysfunction In Cardiac Agingmentioning

confidence: 99%

Dysfunctional mitochondria elicit bioenergetic decline in the aged heart

Mone,

Agyapong,

Morciano

et al. 2024

J Cardiovasc Aging

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Aging represents a complex biological progression affecting the entire body, marked by a gradual decline in tissue function, rendering organs more susceptible to stress and diseases. The human heart holds significant importance in this context, as its aging process poses life-threatening risks. It entails macroscopic morphological shifts and biochemical changes that collectively contribute to diminished cardiac function. Among the numerous pivotal factors in aging, mitochondria play a critical role, intersecting with various molecular pathways and housing several aging-related agents. In this comprehensive review, we provide an updated overview of the functional role of mitochondria in cardiac aging.

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Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling

Cited by 17 publications

References 30 publications

CDK5R1,GSE1,HSPG2andWDFY3as indirect epigenetic‐sensitive genes in atrial fibrillation

CDK5R1,GSE1,HSPG2andWDFY3as indirect epigenetic‐sensitive genes in atrial fibrillation

Mitochondrial Dysfunction: A Roadmap for Understanding and Tackling Cardiovascular Aging

Dysfunctional mitochondria elicit bioenergetic decline in the aged heart

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