Short-chain fatty acid metabolism and multiple effects on cardiovascular diseases

The mitochondria are essential organelles that generate large amounts of ATP via the electron transport chain (ECT). Mitochondrial dysfunction causes reactive oxygen species accumulation, energy stress, and cell death. Endothelial mitochondrial dysfunction is an important factor causing abnormal function of the endothelium, which plays a central role during atherosclerosis development. Atherosclerosis-related risk factors, including high glucose levels, hypertension, ischemia, hypoxia, and diabetes, promote mitochondrial dysfunction in endothelial cells. This review summarizes the physiological and pathophysiological roles of endothelial mitochondria in endothelial function and atherosclerosis.

Mitochondrial dysfunction in vascular endothelial cells and its role in atherosclerosis

Abstract Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of SDH subunits (SDHD and SDHB) in hereditary tumors such as paraganglioma or reduction of SDHB expression in cancer results in matrix succinate accumulation which is transported to cytoplasma and secreted into the extracellular milieu. Excessive cytosolic succinate is known to stabilize hypoxia inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylase. Recent reports indicate that cancer-secreted succinate enhances cancer cell migration and promotes cancer metastasis by activating succinate receptor-1 (SUCNR-1)-mediated signaling and transcription pathways. Cancer-derived extracellular succinate enhances cancer cell and macrophage migration through SUCNR-1 → PI-3 K → HIF-1α pathway. Extracellular succinate induces tumor angiogenesis through SUCNR-1-mediated ERK1/2 and STAT3 activation resulting in upregulation of vascular endothelial growth factor (VEGF) expression. Succinate increases SUCNR-1 expression in cancer cells which is considered as a target for developing new anti-metastasis drugs. Furthermore, serum succinate which is elevated in cancer patients may be a theranostic biomarker for selecting patients for SUCNR-1 antagonist therapy. 

/pdf/cancer-derived-extracellular-succinate-a-driver-of-cancer-3vznlvh8.pdf

Cancer-derived extracellular succinate: a driver of cancer metastasis

Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are limited and their connections to the underlying mechanisms of aging are not fully clear. Here, these connections are explored in terms of the tricarboxylic acid (TCA) cycle (Krebs cycle, citric acid cycle) to suggest reasons for the loss of effectiveness and ways of overcoming it. Specifically, the metabolic interventions deplete acetate and likely reduce the conversion of oxaloacetate to aspartate, thereby inhibiting the mammalian target of rapamycin (mTOR) and upregulating autophagy. Synthesis of glutathione may provide a high-capacity sink for amine groups, facilitating autophagy, and prevent buildup of alpha-ketoglutarate, supporting stem cell maintenance. Metabolic interventions also prevent the accumulation of succinate, thereby slowing DNA hypermethylation, facilitating the repair of DNA double-strand breaks, reducing inflammatory and hypoxic signaling, and lowering reliance on glycolysis. In part through these mechanisms, metabolic interventions may decelerate aging, extending lifespan. Conversely, with overnutrition or oxidative stress, these processes function in reverse, accelerating aging and impairing longevity. Progressive damage to aconitase, inhibition of succinate dehydrogenase, and downregulation of hypoxia-inducible factor-1α, and phosphoenolpyruvate carboxykinase (PEPCK) emerge as potentially modifiable reasons for the loss of effectiveness of metabolic interventions.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/adbi.202300095

The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions.

Glioblastoma (GBM), similar to most cancers, is dependent on fermentation metabolism for the synthesis of biomass and energy (ATP) regardless of the cellular or genetic heterogeneity seen within the tumor. The transition from respiration to fermentation arises from the documented defects in the number, the structure, and the function of mitochondria and mitochondrial-associated membranes in GBM tissue. Glucose and glutamine are the major fermentable fuels that drive GBM growth. The major waste products of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify the microenvironment and are largely responsible for drug resistance, enhanced invasion, immunosuppression, and metastasis. Besides surgical debulking, therapies used for GBM management (radiation, chemotherapy, and steroids) enhance microenvironment acidification and, although often providing a time-limited disease control, will thus favor tumor recurrence and complications. The simultaneous restriction of glucose and glutamine, while elevating non-fermentable, anti-inflammatory ketone bodies, can help restore the pH balance of the microenvironment while, at the same time, providing a non-toxic therapeutic strategy for killing most of the neoplastic cells.

/pdf/metabolic-management-of-microenvironment-acidity-in-1ypv2c6x.pdf

Metabolic management of microenvironment acidity in glioblastoma

Succinate is an important intermediate product of mitochondrial energy metabolism. Recent studies revealed that beyond its known traditional metabolic functions, succinate plays important roles in signal transduction, immunity, inflammation, and posttranslational modification. Recent studies showed that patients and mouse models with cardiovascular disease have high levels of serum succinate and succinate accumulation. Atherosclerosis (As) is the pathological basis of cardiovascular and peripheral vascular diseases, such as coronary heart disease, cerebral infarction, and peripheral vascular disease, and is a major factor affecting human health. This article reviews the progression of succinate in As diseases and its underlying mechanisms.

Succinate: A Novel Mediator to Promote Atherosclerotic Lesion Progression.

Autophagy maintains intracellular homeostasis in the cardiovascular system, including in cardiomyocytes, endothelial cells (ECs), and arterial smooth muscle cells. Mitophagy, a selective autophagy that specifically removes damaged and dysfunctional mitochondria, is particularly important for cardiovascular homeostasis. Dysfunctional mitophagy contributes to cardiovascular disease, particularly atherosclerosis (AS). This review focuses on the advances of regulator mechanisms of mitophagy and its potential roles in AS. The findings are beneficial to understanding the pathological processes of atherosclerotic lesions and provide new ideas for the prevention and clinical treatment of AS.

Mitophagy: Critical Role in Atherosclerosis Progression.

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Succinate: A Novel Mediator to Promote Atherosclerotic Lesion Progression.

Mitophagy: Critical Role in Atherosclerosis Progression.