Boosting mitochondrial metabolism with dietary supplements in heart failure.
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ABSTRACT:
SUBMITTER: O'Brien KD
PROVIDER: S-EPMC9172082 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
Publications
Boosting mitochondrial metabolism with dietary supplements in heart failure.
O'Brien Kevin D KD Tian Rong R
Nature reviews. Cardiology 20211001 10
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Project description:Dietary supplements Metagenome
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Project description:The mitochondrion serves a critical role as a platform for energy transduction, signaling, and cell death pathways relevant to common diseases of the myocardium such as heart failure. This review focuses on the molecular regulatory events and downstream effector pathways involved in mitochondrial energy metabolic derangements known to occur during the development of heart failure.
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Project description:Surveys of mitochondrial disease physicians conducted through the Mitochondrial Medicine Society have shown that virtually all providers recommend a variety of dietary supplements as treatments to their patients in an effort to enhance energy production and reduce oxidative stress. In this survey, we asked patients and their parents about their experiences taking these dietary supplements for mitochondrial disease. The survey was disseminated through the North American Mitochondrial Disease Consortium (NAMDC) and the Rare Disease Clinical Research Network (RDCRN) registries and gathered 162 responses. The study ascertained each patient's mitochondrial disease diagnosis, dietary supplements used, adjunct therapy, and effects of the supplements on symptoms and health. Regardless of the specific underlying mitochondrial disease, the majority of the survey respondents stated they are or have been on dietary supplements. Most patients take more than four supplements primarily coenzyme Q10, l-carnitine, and riboflavin. The majority of patients taking supplements reported health benefits from the supplements. The onset of perceived benefits was between 2weeks to 3months of initiating intake. Supplements seem to be safe, with only 28% of patients experiencing mild side-effects and only 5.6% discontinuing their intake due to intolerance. Only 9% of patients had insurance coverage for their supplements and when paying out of pocket, 95% of them spend up to $500/month. Despite the use of concomitant therapies (prescribed medications, physical therapy, diet changes and other), 45.5% of patients think that dietary supplements are the only intervention improving their symptoms. Some limitations of this study include the retrospective collection of data probably associated with substantial recall bias, lack of longitudinal follow up to document pre- and post-supplement clinical status and second hand reports by parents for children which may reflect parents' subjective interpretation of symptoms severity and supplements effect rather than real patients' experience. More extensive prospective studies will help further elucidate this topic.
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Project description:We conducted RNAseq using mRNA extracted from rat hearts to elucidate the effect of doxorubicin chemotherapy on the heart. Rats were 250g at the start of the treatment protocol. Tissues were collected post five weekly intravenous injections of either sterile saline or 3mg/kg/week doxorubicin. Hearts were excised under deep isoflurane anaesthesia and rapidly frozen with liquid-nitrogen cooled Wallenberger tongs. Total mRNA was extracted with a Qiagen RNeasy fibrous tissue mini kit. Gene set enrichement analysis (GSEA) shows that unlike previously reported, oxidative stress is not involved in the cardiac pathology of our model (reduced cardiac function and atrophy). However, gene sets responsible for mRNA processing, ribosomes and protein synthesis and processing are decreased in doxorubicin-treated rat hearts compared to saline control hearts.
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Project description:In current study, we found that the protein level of MOF in mitochondrial was significantly increased during the course of heart failure. Overexpression of mtMOF induced cardiac hypertrophy and energy metabolism disorder, as well as heart failure. When combined with mtMOF overexpression and SIRT3 deficiency, the acetylation level in cardiomyocytes was significantly upregulated, accompanied with serious enegergy abnormal and cardiac function injury. Mitochondrial substrates of MOF was identified by using acetylated proteomic analysis. We demonstrated that mtMOF and SIRT3 exhibited damage effect by regulating the acetylation level of the common substrate ATP5B. This study clarified the acetyltransferase activity of MOF in mitochondria, providing a new theoretical basis for the acetylation regulation mode of mitochondrial proteins. In addition, we provides a new research idea for exploring the relationship between hyperacetylation and energy metabolism disorder and heart failure.
2024-12-09 | PXD044074 | Pride
Project description:BACKGROUNDWhile mitochondria play an important role in innate immunity, the relationship between mitochondrial dysfunction and inflammation in heart failure (HF) is poorly understood. In this study we aimed to investigate the mechanistic link between mitochondrial dysfunction and inflammatory activation in peripheral blood mononuclear cells (PBMCs), and the potential antiinflammatory effect of boosting the NAD level.METHODSWe compared the PBMC mitochondrial respiration of 19 hospitalized patients with stage D HF with that of 19 healthy participants. We then created an in vitro model of sterile inflammation by treating healthy PBMCs with mitochondrial damage-associated molecular patterns (MitoDAMPs) isolated from human heart tissue. Last, we enrolled patients with stage D HF and sampled their blood before and after taking 5 to 9 days of oral nicotinamide riboside (NR), a NAD precursor.RESULTSWe demonstrated that HF is associated with both reduced respiratory capacity and elevated proinflammatory cytokine gene expressions. In our in vitro model, MitoDAMP-treated PBMCs secreted IL-6 that impaired mitochondrial respiration by reducing complex I activity. Last, oral NR administration enhanced PBMC respiration and reduced proinflammatory cytokine gene expression in 4 subjects with HF.CONCLUSIONThese findings suggest that systemic inflammation in patients with HF is causally linked to mitochondrial function of the PBMCs. Increasing NAD levels may have the potential to improve mitochondrial respiration and attenuate proinflammatory activation of PBMCs in HF.TRIAL REGISTRATIONClinicalTrials.gov NCT03727646.FUNDINGThis study was funded by the NIH, the University of Washington, and the American Heart Association.
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Project description:Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area, there is ≈50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction.
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Project description:AimsMitochondrial fusion and fission are essential processes for preservation of normal mitochondrial function. We hypothesized that fusion proteins would be decreased in heart failure (HF), as the mitochondria in HF have been reported to be small and dysfunctional.Methods and resultsExpression of optic atrophy 1 (OPA1), a mitochondrial fusion protein, was decreased in both human and rat HF, as observed by western blotting. OPA1 is important for maintaining normal cristae structure and function, for preserving the inner membrane structure and for protecting cells from apoptosis. Confocal and electron microscopy studies demonstrated that the mitochondria in the failing hearts were small and fragmented, consistent with decreased fusion. OPA1 mRNA levels did not differ between failing and normal hearts, suggesting post-transcriptional control. Simulated ischaemia in the cardiac myogenic cell line H9c2 cells reduced OPA protein levels. Reduction of OPA1 expression with shRNA resulted in increased apoptosis and fragmentation of the mitochondria. Overexpression of OPA1 increased mitochondrial tubularity, but did not protect against simulated ischaemia-induced apoptosis. Cytochrome c release from the mitochondria was increased both with reduction in OPA1 and with overexpression of OPA1.ConclusionThis is the first report, to our knowledge, of changes in mitochondrial fusion/fission proteins in cardiovascular disease. These changes have implications for mitochondrial function and apoptosis, contributing to the cell loss which is part of the downward progression of the failing heart.
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