Intracellular sodium elevation reprograms cardiac metabolism

Aksentijević, Dunja; Karlstaedt, Anja; Basalay, Marina; O’Brien, Brett A.; Sánchez-Tatay, David; Eminaga, Seda; Thakker, Alpesh; Tennant, Daniel A.; Fuller, William; Eykyn, Thomas R.; Taegtmeyer, Heinrich; Shattock, Michael J.

doi:10.1038/s41467-020-18160-x

Cited by 50 publications

(52 citation statements)

References 50 publications

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“…Sodium (Na + ) and calcium (Ca 2+ ) ions are closely linked to HF. Elevated intracellular Na + can lead to cardiac energy metabolic shift from FAO to glycolysis ( 38 ). The renin-angiotensin-aldosterone (RAAS) system has evolved to retain Na + homeostasis and RAAS-blockers have been widely used in HF therapy.…”

Section: Metabolic Remodeling From Normal To Failing Heart Is Both Cause and Effect Of Heart Failurementioning

confidence: 99%

Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities

Zhao

Wang

2021

Front. Cardiovasc. Med.

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Heart failure (HF) patients often suffer from multiple comorbidities, such as diabetes, atrial fibrillation, depression, chronic obstructive pulmonary disease, and chronic kidney disease. The coexistance of comorbidities usually leads to multi morbidity and poor prognosis. Treatments for HF patients with multi morbidity are still an unmet clinical need, and finding an effective therapy strategy is of great value. HF can lead to comorbidity, and in return, comorbidity may promote the progression of HF, creating a vicious cycle. This reciprocal correlation indicates there may be some common causes and biological mechanisms. Metabolism remodeling and chronic inflammation play a vital role in the pathophysiological processes of HF and comorbidities, indicating metabolism and inflammation may be the links between HF and comorbidities. In this review, we comprehensively discuss the major underlying mechanisms and therapeutic implications for comorbidities of HF. We first summarize the potential role of metabolism and inflammation in HF. Then, we give an overview of the linkage between common comorbidities and HF, from the perspective of epidemiological evidence to the underlying metabolism and inflammation mechanisms. Moreover, with the help of bioinformatics, we summarize the shared risk factors, signal pathways, and therapeutic targets between HF and comorbidities. Metabolic syndrome, aging, deleterious lifestyles (sedentary behavior, poor dietary patterns, smoking, etc.), and other risk factors common to HF and comorbidities are all associated with common mechanisms. Impaired mitochondrial biogenesis, autophagy, insulin resistance, and oxidative stress, are among the major mechanisms of both HF and comorbidities. Gene enrichment analysis showed the PI3K/AKT pathway may probably play a central role in multi morbidity. Additionally, drug targets common to HF and several common comorbidities were found by network analysis. Such analysis has already been instrumental in drug repurposing to treat HF and comorbidity. And the result suggests sodium-glucose transporter-2 (SGLT-2) inhibitors, IL-1β inhibitors, and metformin may be promising drugs for repurposing to treat multi morbidity. We propose that targeting the metabolic and inflammatory pathways that are common to HF and comorbidities may provide a promising therapeutic strategy.

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Section: Metabolic Remodeling From Normal To Failing Heart Is Both Cause and Effect Of Heart Failurementioning

confidence: 99%

Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities

Zhao

Wang

2021

Front. Cardiovasc. Med.

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“…Calcium ions are important second messengers of cell metabolism, and can stimulate ATP synthesis in mitochondria by activating diverse enzymes in the electron transport chain (42). The influx of Ca 2+ into mitochondria through the Na + /Ca 2+ exchange channel in the mitochondria membrane has been shown to activate ATP generation in mouse heart cells (43). In thraustochytrids, ion exchange channels are a major response mechanism for osmotic stress (44), which could have altered intracellular Ca 2+ levels and led to increased respiration in the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

ATP drives efficient terpene biosynthesis in marine thraustochytrids

Zhang

Mernitz

et al. 2020

Preprint

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Understanding carbon flux-controlling mechanisms in a tangled metabolic network is an essential question of cell metabolism. Secondary metabolism, such as terpene biosynthesis, has evolved with low carbon flux due to inherent pathway constraints. Thraustochytrids are a group of heterotrophic marine unicellular protists, and can accumulate terpenoids under the high salt condition in their natural environment. However, the mechanism behind the terpene accumulation is not well understood. Here we show that terpene biosynthesis in Thraustochytrium sp. ATCC 26185 is constrained by local thermodynamics in the mevalonate pathway. Thermodynamic analysis reveals the metabolite limitation in the nondecarboxylative Claisen condensation of acetyl-CoA to acetoacetyl-CoA step catalyzed by the acetyl-CoA acetyltransferase (ACAT). Through a sodium elicited mechanism, higher respiration leads to increased ATP investment into the mevalonate pathway, providing a strong thermodynamic driving force for enhanced terpene biosynthesis. The proteomic analysis further indicates that the increased ATP demands are fulfilled by shifting energy generation from carbohydrate to lipid metabolism. This study demonstrates a unique strategy in nature using ATP to drive a low-flux metabolic pathway, providing an alternative solution for efficient terpene metabolic engineering.IMPORTANCETerpenoids are a large class of lipid molecules with important biological functions, and diverse industrial and medicinal applications. Metabolic engineering for terpene production has been hindered by the low flux distribution to its biosynthesis pathway. In practice, a high substrate load is generally required to reach high product titers. Here we show that the mevalonate-derived terpene biosynthesis is constrained by local pathway thermodynamics, which can only be partially relieved by increasing substrate levels. Through comparative proteomic and biochemical analyses, we discovered a unique mechanism for high terpene accumulation in marine protists thraustochytrids. Through a sodium induced mechanism, thraustochytrids shift their energy metabolism from carbohydrate to lipid metabolism for enhanced ATP production, providing a strong thermodynamic driving force for efficient terpene biosynthesis. This study reveals an important mechanism in eukaryotes to overcome the thermodynamic constraint in low-flux pathways by increased ATP consumption. Engineering energy metabolism thus provides an important alternative to relieve flux constraints in low-flux and energy-consuming pathways.

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“…Indeed, it has been recently demonstrated that acute inhibition of NCLX ameliorates metabolic changes in failing hearts [ 70 ]. This pathway could be inhibited by pharmacological targeting of CI by rotenone or piericidin A, or by genetic ablation of CI subunits.…”

Section: Ros In Acute Hypoxiamentioning

confidence: 99%

Generation of Reactive Oxygen Species by Mitochondria

2021

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Reactive oxygen species (ROS) are series of chemical products originated from one or several electron reductions of oxygen. ROS are involved in physiology and disease and can also be both cause and consequence of many biological scenarios. Mitochondria are the main source of ROS in the cell and, particularly, the enzymes in the electron transport chain are the major contributors to this phenomenon. Here, we comprehensively review the modes by which ROS are produced by mitochondria at a molecular level of detail, discuss recent advances in the field involving signalling and disease, and the involvement of supercomplexes in these mechanisms. Given the importance of mitochondrial ROS, we also provide a schematic guide aimed to help in deciphering the mechanisms involved in their production in a variety of physiological and pathological settings.

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Intracellular sodium elevation reprograms cardiac metabolism

Cited by 50 publications

References 50 publications

Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities

Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities

ATP drives efficient terpene biosynthesis in marine thraustochytrids

Generation of Reactive Oxygen Species by Mitochondria

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