Effect of Aging on Mitochondrial Energetics in the Human Atria
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PROVIDER: PRJNA726259 | ENA |
REPOSITORIES: ENA
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Project description:Energy production in myocardial cells occurs mainly in the mitochondrion. Although alterations in mitochondrial functions in the senescent heart have been documented, the molecular bases for the aging-associated decline in energy metabolism in the human heart are not fully understood. The purpose of our study was to identify aging-related transcriptional changes in genes coding for mitochondrial proteins involved in substrate metabolism, oxidative phosphorylation system (OXPHOS), and the tricarboxylic acid (TCA) cycle, and to correlate these with the functional changes in the OXPHOS in human atrial appendage tissue from adult and aged patients free of atrial pathologies.
2021-04-30 | GSE173608 | GEO
Project description:Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in the creatine kinase and ATP synthesis. Accompanying these metabolic derangements, quantitative electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.
2022-07-17 | GSE180313 | GEO
Project description:Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy
| PRJNA747806 | ENA
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| S-EPMC5905598 | biostudies-literature
Project description:To investigate the effect of aging on mitochondrial gene expression we isolated liver mitochondria from 4 12-week and 4 65-week C57BL/6N WT mice. We then isolated RNA and prepared the barcoded library using PCR-cDNA Barcoding Kit SQK-PCB109 and ran it on MinIOn R9.4.1 Flow cells.
2022-07-17 | GSE208177 | GEO
Project description:Aging is the progressive decline in organismal function that leads to an increased risk of multiple diseases and mortality. The molecular basis of this decline is unknown. Using quantitative PCR for mitochondrial mRNA from multiple tissues from the same animals, we found that the rate of change in mouse mitochondrial expression is tissue-specific, with cardiac expression declining early (8-10 months), adipose expression declining late (25-30 months), and no change in kidney or skin. In cardiac tissue, mitochondria-derived mRNA levels declined more slowly than nuclear encoded mRNAs, suggesting a potential dysregulation. These changes were independent of alteration in mitochondrial number, as measured by quantitative PCR of mitochondrial DNA and citrate synthase activity. We found no change in the variability between mitochondrial mRNA levels with age, suggesting that the changes are not due to random dysregulation at the level of gene expression. Caloric restriction (CR), a lifespan-extending intervention proposed to act through mitochondrial biogenesis, delayed the decline in both cardiac and adipose mitochondrial mRNA levels of F344 rats. CR caused an increase in citrate synthase activity but did not alter mitochondrial DNA content, indicating increased translation or reduced turnover of mitochondrial proteins. These results demonstrate that mitochondrial gene expression changes with age are not coupled to mitochondrial number, are likely to be regulated, and are governed by tissue-specific processes. These findings indicate that aging is neither a programmed organism-wide change orchestrated in a top-down fashion nor a product of random dysregulation of gene expression but that tissue-specific factors may independently control aging in different organ compartments. Keywords: aging Cardiac ventricle total RNA from 10 young (4-6 month) and 10 young (25-28 month) mice were compared.
2015-07-03 | E-GEOD-12480 | biostudies-arrayexpress
Project description:Effect of aging on mitochondrial gene expression using C57BL/6N liver mitochondria
| PRJNA858664 | ENA
Project description:Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data shows that aging promotes an increase in localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and has a mechanistic link to T cell cytokine production. More specifically, mitoSTAT3 increased activity of aging T cell mitochondria due to STAT3’s effect on complex II. Limiting mitoSTAT3 using a mitochondria targeted curcuminoid, Mtcur-1, lowered complex II activity, prevented age-induced changes in mitochondrial dynamics and function, and reduced proinflammatory Th17 inflammation. Exogenous expression of the constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and function in T cells from older adults and partially recapitulated aging-induced cytokine profiles. Our data shows the mechanistic link among mitoSTAT3, mitochondrial dynamics,function and T cell cytokine production.
2023-10-17 | GSE241492 | GEO
Project description:Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understand the aging process. Using a model that carries a proofreading defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging including anemia, lymphopenia and myeloid lineage skewing. However, in contrast to physiologic stem cell aging, rapidly accumulating mitochondrial DNA mutations displayed little involvement of the hematopoietic stem cell pool but rather with distinct differentiation blocks and/or disappearance of downstream progenitors. Hematopoietic stem cells (HSC) has been sorted out from midaged wildtype and mutator mice and compared with stem cells sorted from young and and old wt mice
2011-05-06 | E-GEOD-27686 | biostudies-arrayexpress
Project description:Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the ‘CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. Strikingly, this pro-longevity metabolic state is regulated cell-nonautonomously by CRTC-1 in the nervous system. CRTC-1/CREB act antagonistically with the functional PPARα ortholog, NHR-49 to promote distinct peripheral metabolic programs. Neuronal CRTC-1 drives mitochondrial fragmentation in distal tissues and suppresses the effect of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that transcriptional control of neuronal signals can override enzymatic regulation of metabolism in peripheral tissues. Central perception of energetic state therefore represents a target to promote healthy aging.
2015-02-27 | GSE58931 | GEO