Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, is associated with neuroinflammation. Periodontal disease increases with age; 70.1% of adults 65 years and older have periodontal problems. However, the P. gingivalis- lipopolysaccharide (LPS)induced mitochondrial dysfunction in neurodegenerative diseases remains elusive. In this study, we investigated the possible role of P. gingivalis-LPS in mitochondrial dysfunction during neurodegeneration. We found that P. gingivalis-LPS treatment activated toll-like receptor (TLR) 4 signaling and upregulated the expression of Alzheimer’s disease-related dementia and neuroinflammatory markers. Furthermore, the LPS treatment significantly exacerbated the production of reactive oxygen species and reduced the mitochondrial membrane potential. Our study highlighted the pivotal role of P. gingivalis-LPS in the repression of serum response factor (SRF) and its co-factor p49/STRAP that regulate the actin cytoskeleton. The LPS treatment repressed the genes involved in mitochondrial function and biogenesis. P. gingivalis-LPS negatively altered oxidative phosphorylation and glycolysis and reduced total adenosine triphosphate (ATP) production. Additionally, it specifically altered the mitochondrial functions in complexes I, II, and IV of the mitochondrial electron transport chain. Thus, it is conceivable that P. gingivalis-LPS causes mitochondrial dysfunction through oxidative stress and inflammatory events in neurodegenerative diseases.

Aging is a major risk factor for cardiovascular disease, driving progressive structural and functional decline of the myocardium. Mitochondria, the primary source of ATP through oxidative phosphorylation, are essential for cardiac contractility, calcium homeostasis, and redox balance. In the aging heart, mitochondria show morphological alterations including cristae disorganization, swelling, and fragmentation, along with reduced OXPHOS efficiency. These defects increase proton leak, lower ATP production, and elevate reactive oxygen species (ROS), causing oxidative damage. Concurrent disruptions in mitochondrial fusion and fission further impair turnover and quality control, exacerbating mitochondrial dysfunction and cardiac decline. Serum response factor (SRF) signaling, a crucial regulator of cytoskeletal and metabolic gene expression, plays a key role in modulating mitochondrial function during cardiac aging. Dysregulation of SRF impairs mitochondrial adaptability, contributing to dysfunction. Additionally, reduced levels of nicotinamide adenine dinucleotide (NAD⁺) hinder sirtuin-dependent deacetylation, further compromising mitochondrial efficiency and stress resilience. These cumulative defects activate regulated cell death pathways, leading to cardiomyocyte loss, fibrosis, and impaired diastolic function. Mitochondrial dysfunction therefore serves as both a driver and amplifier of cardiac aging, accelerating the transition toward heart failure. This narrative review aims to provide a comprehensive overview of mitochondrial remodeling in the aging myocardium, examining the mechanistic links between mitochondrial dysfunction and myocardial injury. We also discuss emerging therapeutic strategies targeting mitochondrial bioenergetics and quality control as promising approaches to preserve cardiac function and extend cardiovascular health span in the aging population.

In radiotherapy treatment of thoracic, breast and chest wall tumors, the heart may be included (partially or fully) in the radiation field. As a result, patients may develop radiation-induced heart disease (RIHD) several years after exposure to radiation. There are few methods available to prevent or reverse RIHD and the biological mechanisms remain poorly understood. In order to further study the effects of radiation on the heart, we developed a model of local heart irradiation in rats using an image-guided small animal conformal radiation therapy device (SACRTD) developed at our institution. First, Monte Carlo based simulations were used to design an appropriate collimator. EBT-2 films were used to measure relative dosimetry, and the absolute dose rate at the isocenter was measured using the AAPM protocol TG-61. The hearts of adult male Sprague-Dawley rats were irradiated with a total dose of 21 Gy. For this purpose, rats were anesthetized with isoflurane and placed in a custom-made vertical rat holder. Each heart was irradiated with a 3-beam technique (one AP field and 2 lateral fields), with each beam delivering 7 Gy. For each field, the heart was visualized with a digital flat panel X-ray imager and placed at the isocenter of the 1.8 cm diameter beam. In biological analysis of radiation exposure, immunohistochemistry showed γH2Ax foci and nitrotyrosine throughout the irradiated hearts but not in the lungs. Long-term follow-up of animals revealed histopathological manifestations of RIHD, including myocardial degeneration and fibrosis. The results demonstrate that the rat heart irradiation technique using the SACRTD was successful and that surrounding untargeted tissues were spared, making this approach a powerful tool for in vivo radiobiological studies of RIHD. Functional and structural changes in the rat heart after local irradiation are ongoing.

The sirtuin-1 (SIRT1) gene contains multiple exons that usually undergo alternative splicing. The exclusion of one or more exons causes domain loss in the alternatively spliced isoforms and may change their functions. However, it is not completely established to what extent the loss of a non-catalytic domain could affect its regulatory function. Using muscle cells and SIRT1-knockout cells, we examined the function of the constitutively spliced isoform (SIRT1-v1) versus the alternatively spliced isoforms SIRT1-v2 and SIRT1-v3 that had lost part of the N-terminal region. Our data indicate that partial loss of the N-terminal domains in SIRT1-v2 and SIRT1-v3 attenuated their function. The full-length SIRT1-v1 significantly increased the oxidative phosphorylation and ATP production rate. Furthermore, SIRT1-v1 specifically upregulated the mitochondrial respiratory complex I without affecting the activity of complexes II, III, and IV. Additionally, domain loss affected the regulation of site-specific lysine acetylation in the histone H4 protein, the gene expression of respiratory complex I subunits, and the metabolic balance of oxidative phosphorylation versus glycolysis. Since alternatively spliced isoforms tend to increase with advancing age, the impact of SIRT1 isoforms on mitochondrial respiratory complexes warrants further investigation.

Background: Alternative splicing is an important mechanism of transcriptomic and proteomic diversity and is progressively involved in cardiovascular disease (CVD) pathogenesis. Serum response factor (SRF), a critical transcription factor in cardiac development and function, may itself undergo splicing regulation, potentially altering its function in disease states. Objective: The objective of this study is to identify SRF-associated alternative splicing events in cardiac pathological conditions and examine regulatory interactions with splicing factors using RNA-seq data. Methods: Three human heart RNA-seq databases (PRJNA198165, PRJNA477855, PRJNA678360) were used, comprising various cardiac conditions like non-ischemic cardiomyopathy (NICM), ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), and heart failure with reduced ejection fraction (HFrEF), with and without left ventricular assist device (LVAD) support. Splicing events were identified using the rMATS tool, and correlation analyses were performed between SRF and predicted splicing factors. Functional enrichment of SRF-correlated genes was assessed via Gene Ontology (GO) and KEGG pathways. Results: The skipped exon (SE) events were the predominant splicing type across all datasets. SRF chr6, including (Exon 2, 43,173,847–43,174,113), (Exon 4, 43,176,548–43,176,667), and (Exon 5, 43,178,294-43,178,485), were most frequently involved in SE and mutually exclusive exon (MXE) events across multiple heart failure subtypes. Correlation analysis revealed strong positive associations between SRF and several splicing factors (HNRNPL, HNRNPD, SRSF5, and SRSF8). GO and KEGG analyses revealed enrichment of muscle development, sarcomere structure, lipid metabolism, and immune signaling pathways. Conclusions: Our study shows that SRF is subject to extensive alternative splicing in heart failure, particularly at Exon 2 and Exon 5, suggesting isoform-specific roles in cardiac remodeling. The strong co-expression with specific splicing factors delineates a regulatory axis that may explain the pathological transcriptome in cardiomyopathy. These findings provide a foundation for exploring splicing-based biomarkers and therapeutic targets in cardiac pathology for SRF.

Purpose: Heart failure (HF) impairs physical performance and increases the incidence of orthostatic hypotension (OH). Individuals with OH have a higher risk of falls, which are a major source of morbidity and mortality in older adults. Dietary protein supplementation can improve physical performance in healthy older adult individuals; however, its effect on OH in older adult patients with HF is unknown. Methods: Twenty-one older adult patients with mild-to-moderate HF were randomized to placebo or protein supplementation. Dietary protein was supplemented with whey protein so the total protein intake for each participant was 1.2 g/kg bodyweight/day, plus 1 g/day of the amino acid l-carnitine for 16 weeks. Susceptibility to OH was assessed using a head-up tilt test, blood markers, and a functional test (6 min walk) at baseline and 16 weeks. Results: There were no differences in tilt test responses or 6 min walk test (6MWT) distances. The protein-supplement group had a significant increase in 6MWT pulse pressures post-walk after 16 weeks of treatment as compared to placebo. However, the tachycardia observed at baseline after 6MWT in the protein group was not seen at the end of the study. There was also a trend towards lower levels of brain naturetic peptide (proBNP) in the protein group vs. placebo at 16 weeks. Conclusions: The improved pulse-pressure response to exertion and positive trends in proBNP in this pilot study suggest that dietary supplementation may improve cardiovascular function and general health in individuals with HF and that larger future studies are justifiable.