Succinate

Background

Succinate is a dicarboxylic acid anion that plays a crucial role as an intermediate in cellular metabolism. It is a fundamental component of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, which is central to aerobic respiration and energy production within cells. Succinate is found in virtually all living organisms, from bacteria to humans, highlighting its conserved and essential biological functions. Beyond its metabolic role, succinate has emerged as an important signaling molecule, influencing various cellular processes.

Biological Basis

Within the mitochondria, succinate is produced from succinyl-CoA by succinyl-CoA synthetase. It is then oxidized to fumarate by the enzyme succinate dehydrogenase (SDH), which is a complex II of the electron transport chain. This dual role as both a TCA cycle enzyme and a component of the electron transport chain underscores its critical position in cellular energy generation. The conversion of succinate to fumarate directly contributes electrons to the electron transport chain, driving ATP synthesis. Furthermore, succinate acts as a signaling molecule, accumulating under conditions of hypoxia or metabolic stress. High levels of succinate can inhibit prolyl hydroxylase enzymes, leading to the stabilization of hypoxia-inducible factor (HIF), a key regulator of cellular responses to low oxygen. This intricate interplay connects metabolic status directly to gene expression and cellular adaptation.

Clinical Relevance

The vital role of succinate in metabolism and signaling makes its dysregulation relevant to numerous human diseases. Genetic mutations in the genes encoding succinate dehydrogenase (SDH) subunits (SDHA, SDHB, SDHC, SDHD, SDHAF2) are associated with various conditions, including paragangliomas, pheochromocytomas, and gastrointestinal stromal tumors (GISTs). These mutations lead to succinate accumulation, which can drive tumorigenesis through the pseudohypoxia pathway. Elevated succinate levels are also implicated in mitochondrial diseases, neurodegenerative disorders such as Parkinson’s disease, and even cardiovascular conditions like hypertension and heart failure, where it can contribute to oxidative stress and inflammation. Understanding succinate metabolism offers potential avenues for therapeutic intervention in these conditions.

Social Importance

The widespread impact of succinate on human health translates into significant social importance. Research into succinate’s roles in metabolism and signaling is critical for developing new diagnostic tools and therapeutic strategies for a range of diseases, from rare genetic disorders to common chronic conditions. Public awareness of metabolic health, including the importance of a balanced diet and lifestyle in influencing metabolic pathways involving succinate, can empower individuals to make informed choices that promote well-being. Furthermore, the study of succinate contributes to a broader understanding of fundamental biological processes, impacting areas such as aging research, cancer biology, and the development of new pharmaceuticals targeting metabolic pathways.

Limitations

Methodological and Statistical Constraints

Research into the genetic influences on succinate levels often faces challenges related to study design and statistical power. Many initial discoveries rely on genome-wide association studies (GWAS) that, despite large sample sizes, may still be underpowered to detect variants with small effect sizes, leading to potential false negatives. Conversely, statistically significant findings, particularly from smaller cohorts or early-stage discovery studies, can suffer from effect-size inflation, where the reported genetic effect on succinate is stronger than its true biological impact, making replication in independent populations crucial for validation. The reliance on specific cohort designs can also introduce biases, as participants may share common environmental exposures or lifestyle factors that confound the observed genetic associations with succinate levels.

Furthermore, the generalizability of findings is often constrained by the specific characteristics of the study populations. Replication gaps are common, where genetic associations observed in one cohort fail to achieve significance in others, highlighting the need for more diverse and larger validation studies to confirm initial findings. This variability can stem from differences in population structure, environmental factors, or even the methodologies used to measure succinate, all of which complicate the consistent identification of robust genetic determinants. A thorough understanding of these statistical and design limitations is essential for interpreting the strength and reliability of reported genetic associations with succinate.

Phenotypic Definition and Population Generalizability

Defining and consistently measuring succinate levels across diverse populations presents a significant limitation in genetic studies. Succinate, as an intermediate metabolite, can fluctuate based on numerous physiological states, dietary intake, and time of sample collection, making its precise and reproducible quantification challenging. Variations in assay techniques, sample handling, and normalization procedures across different research groups can introduce substantial measurement error and phenotypic heterogeneity, obscuring true genetic signals and complicating comparisons between studies. This lack of standardized phenotyping can lead to inconsistent results and difficulties in identifying robust genetic variants associated with succinate.

Moreover, the vast majority of genetic research on succinate has historically focused on populations of European descent, raising significant concerns about generalizability. Genetic architectures, allele frequencies, and linkage disequilibrium patterns can vary considerably across different ancestral groups, meaning that genetic variants influencing succinate in one population may not have the same effect, or even be present, in another. This ancestry bias limits the applicability of current findings to a global population and underscores the need for more inclusive and diverse cohorts to fully map the genetic landscape of succinate regulation and ensure equitable advancements in personalized health.

Environmental and Gene–Environment Interactions

The regulation of succinate levels is profoundly influenced by a complex interplay of genetic and non-genetic factors, presenting a significant limitation in fully elucidating its heritability. Environmental factors such as diet, exercise, gut microbiome composition, and exposure to various xenobiotics can substantially modulate succinate concentrations, often interacting with genetic predispositions in ways that are not fully understood. Disentangling these intricate gene–environment (GxE) interactions is challenging, as current study designs frequently struggle to capture the full spectrum of environmental exposures and their dynamic effects on succinate metabolism. This complexity contributes to the phenomenon of “missing heritability,” where identified genetic variants only explain a fraction of the observed familial resemblance in succinate levels.

Significant knowledge gaps remain regarding the precise molecular mechanisms through which environmental cues modify genetic effects on succinate, or how specific genetic variants alter an individual’s response to environmental stimuli. For instance, while certain diets might impact succinate, the genetic variants that modify this impact are often not fully characterized. Addressing these gaps requires more sophisticated study designs that integrate detailed environmental phenotyping with comprehensive genetic analyses, alongside functional studies to uncover the underlying biological pathways. Without a deeper understanding of these multifaceted interactions, our ability to predict succinate levels and related health outcomes based purely on genetic information remains incomplete.

Variants

Variants across several genes contribute to diverse cellular functions, including metabolite transport, inflammation, autophagy, and extracellular matrix remodeling, all of which can influence cellular succinate levels and signaling pathways. The_SLC16A3_gene encodes Monocarboxylate Transporter 4 (MCT4), a protein primarily responsible for exporting lactate and protons from highly glycolytic cells, but which can also transport other monocarboxylates like pyruvate and potentially succinate itself. The intronic variantrs12453976 within _SLC16A3_may affect gene expression or splicing efficiency, thereby altering the amount or activity of MCT4 and consequently impacting the cellular flux and extracellular availability of succinate, a crucial metabolic signal and inflammatory mediator.

The _NEK7_ gene, encoding NIMA-related kinase 7, is a critical regulator of cell division and a key component in the activation of the NLRP3 inflammasome. This inflammasome is a multi-protein complex that senses cellular danger signals and triggers robust inflammatory responses by activating caspases and promoting the release of cytokines like IL-1β. The intronic variant rs111428936 in _NEK7_could modulate its expression or function, thereby influencing the threshold for NLRP3 inflammasome activation. Given that succinate accumulation is a known trigger for NLRP3 inflammasome activation, a variant affecting_NEK7_could significantly alter inflammatory responses in conditions characterized by elevated succinate, such as ischemia-reperfusion injury or metabolic stress.

Further impacting cellular homeostasis are variants in _ATG10_, _ADAMTS19_, and _SEMA6D_. _ATG10_ is an essential gene for autophagy, the process by which cells degrade and recycle damaged cellular components, including mitochondria. The intronic variant rs2897554 in _ATG10_could impair autophagic efficiency, leading to the accumulation of dysfunctional mitochondria, which are major producers of succinate, especially under stress conditions._ADAMTS19_ encodes an extracellular matrix protease involved in tissue remodeling and development, while _SEMA6D_ encodes Semaphorin 6D, a signaling molecule important for cell guidance, immune responses, and angiogenesis. Intronic variants rs11242001 in _ADAMTS19_ and rs1618196 in _SEMA6D_may alter the expression or function of these proteins, potentially affecting the tissue microenvironment and cell-cell communication, which can indirectly influence metabolic states and inflammatory signaling pathways modulated by succinate.

Lastly, the intergenic variant rs7028056 is located between the pseudogenes _UBE2V1P10_ and _STK33P1_. While pseudogenes are typically non-coding, some can exert regulatory effects on nearby functional genes or act as RNA sponges. _UBE2V1_ (the functional counterpart to _UBE2V1P10_) is involved in ubiquitination, a critical process for protein degradation and signal transduction, and _STK33_ (the functional counterpart to _STK33P1_) is a kinase involved in cell survival. Although the direct impact of rs7028056 on succinate metabolism is less characterized, alterations in these fundamental cellular processes, even through pseudogene-mediated regulation, could subtly influence mitochondrial function, protein quality control, and overall metabolic resilience, thereby indirectly affecting succinate dynamics.

Key Variants

RS ID	Gene	Related Traits
rs12453976	SLC16A3	malate measurement N-acetylserine measurement succinate measurement
rs11242001	ADAMTS19	succinate measurement
rs111428936	NEK7	succinate measurement
rs7028056	UBE2V1P10 - STK33P1	succinate measurement
rs1618196	SEMA6D	succinate measurement
rs2897554	ATG10	succinate measurement

Biological Background

Succinate: A Core Metabolite in Cellular Energy Production

Succinate is a crucial dicarboxylic acid that plays a central role in cellular energy metabolism as an intermediate of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle. Within the mitochondria, succinate is produced from succinyl-CoA and subsequently oxidized to fumarate by the enzyme succinate dehydrogenase (SDH). ^[1] This metabolic step is unique as SDHis the only enzyme in the TCA cycle that is also an integral component of the mitochondrial electron transport chain (Complex II), directly linking the cycle to oxidative phosphorylation and ATP synthesis.^[1]The transfer of electrons from succinate to ubiquinone viaSDHis fundamental for generating the proton gradient across the inner mitochondrial membrane, which powers ATP synthase, making succinate a vital contributor to aerobic energy production.

The SDH complex is composed of four subunits: SDHA, SDHB, SDHC, and SDHD, along with two assembly factors, SDHAF1 and SDHAF2. ^[1]Each subunit plays a specific role in enzyme function and structural integrity, ensuring the efficient conversion of succinate to fumarate. This enzymatic activity is paramount for maintaining metabolic flux and redox balance within the cell, as disruptions can lead to significant metabolic shifts. The precise regulation of succinate metabolism through theSDH complex is therefore essential for cellular viability and the proper functioning of high-energy-demand tissues. ^[1]

Succinate as a Signaling Molecule and Oncometabolite

Beyond its role in energy metabolism, succinate functions as a signaling molecule, modulating various physiological processes, and is recognized as an “oncometabolite”.^[2]Succinate can exit the mitochondrial matrix and accumulate in the cytoplasm and extracellular space, where it acts as an endogenous ligand for the G-protein coupled receptorSUCNR1 (also known as GPR91). ^[3] Activation of SUCNR1by succinate mediates diverse cellular responses, including inflammatory processes, angiogenesis, blood pressure regulation, and immune cell activation, highlighting its broader impact on systemic homeostasis.^[3]

Furthermore, succinate plays a critical role in cellular adaptation to hypoxia. Under low oxygen conditions, succinate can accumulate and inhibit alpha-ketoglutarate-dependent dioxygenases, such as prolyl hydroxylases (PHDs).^[1] The inhibition of PHDs stabilizes hypoxia-inducible factor (HIF) transcription factors, leading to the activation of genes involved in angiogenesis, erythropoiesis, and metabolic reprogramming, enabling cells to survive and proliferate in oxygen-deprived environments. ^[2]This mechanism is particularly relevant in cancer, where succinate accumulation, often due to genetic mutations, contributes to tumor growth and metastasis by promoting pro-tumorigenic signaling pathways.

Genetic and Epigenetic Regulation of Succinate Metabolism

Genetic alterations profoundly impact succinate metabolism and its downstream effects. Mutations in genes encoding the subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD) and fumarate hydratase (FH), an enzyme that acts downstream of SDHin the TCA cycle, lead to succinate accumulation within cells.^[1]These genetic defects disrupt the normal metabolic flux, preventing succinate’s efficient conversion to fumarate and subsequent steps in the TCA cycle. Such disruptions are associated with specific hereditary cancer syndromes, where the buildup of succinate acts as a metabolic driver for tumorigenesis.^[1]

The elevated levels of succinate, particularly in the context ofSDH and FHdeficiencies, have significant epigenetic consequences. Succinate acts as a competitive inhibitor of various alpha-ketoglutarate-dependent dioxygenases, including the Ten-Eleven Translocation (TET) family of DNA demethylases and Jumonji C domain-containing histone demethylases.^[2] Inhibition of these enzymes leads to widespread alterations in epigenetic marks, such as DNA hypermethylation and changes in histone methylation patterns. These epigenetic modifications can profoundly impact gene expression, silence tumor suppressor genes, and alter cellular identity, contributing to malignant transformation and tumor progression. ^[2]

Systemic and Pathophysiological Consequences of Succinate Dysregulation

Dysregulation of succinate metabolism is directly implicated in a range of pathophysiological processes, most notably in specific forms of cancer. Mutations inSDH subunits are a well-established cause of paragangliomas and pheochromocytomas, rare neuroendocrine tumors. ^[1] Similarly, mutations in FHlead to hereditary leiomyomatosis and renal cell carcinoma, where succinate and fumarate accumulation drives oncogenic processes. These accumulations disrupt cellular homeostasis by altering redox balance, inducing pseudohypoxia, and triggering proliferative signaling pathways, leading to uncontrolled cell growth and tumor development.^[2]

Beyond cancer, systemic alterations in succinate levels or its signaling pathways have broader implications for human health. Elevated succinate has been linked to inflammatory diseases, cardiovascular dysfunction, and kidney disease progression.^[3]For instance, extracellular succinate, through its interaction withSUCNR1, can promote inflammation and tissue injury in various organs. Understanding these systemic consequences and the complex interplay between succinate metabolism, genetic predispositions, and environmental factors is crucial for elucidating disease mechanisms and developing targeted therapeutic strategies.^[3]

Pathways and Mechanisms

Succinate in Core Energy Metabolism and Catabolism

Succinate serves as a crucial intermediate within the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, which is central to aerobic respiration. Within the mitochondrial matrix, succinate is oxidized to fumarate by the enzyme succinate dehydrogenase (SDH), a complex that is also part of the electron transport chain (Complex II). This reaction directly contributes electrons to the ubiquinone pool, which are then channeled through oxidative phosphorylation to generate adenosine triphosphate (ATP), the primary energy currency of the cell. The precise regulation ofSDHactivity and succinate flux through the TCA cycle is vital for maintaining cellular energy homeostasis and responding to varying metabolic demands.

Beyond its role in energy generation, succinate participates in various catabolic pathways, facilitating the breakdown of carbohydrates, fats, and proteins into forms that can enter the TCA cycle. It acts as a nexus, connecting different metabolic arms and ensuring efficient nutrient utilization. The levels of succinate are tightly controlled through the balanced activity of the enzymes that produce it (from succinyl-CoA) and those that consume it (SDH), reflecting the cell’s metabolic state and nutrient availability.

Succinate as a Signaling Metabolite and Regulator of Gene Expression

Emerging evidence highlights succinate’s role not merely as a metabolic intermediate but also as an important signaling molecule that influences cellular processes. Succinate can act as an extracellular ligand for the G-protein coupled receptorSUCNR1(also known as GPR91), initiating intracellular signaling cascades upon binding. This receptor-mediated signaling can influence diverse physiological responses, including blood pressure regulation, immune cell function, and adipose tissue metabolism. Intracellularly, succinate accumulation can inhibit key alpha-ketoglutarate-dependent dioxygenases, such as prolyl hydroxylases (PHD) and histone lysine demethylases (KDM), thereby modulating the activity of transcription factors like hypoxia-inducible factor (HIF) and altering gene expression patterns in response to metabolic shifts.

The inhibition of PHDby succinate stabilizesHIF-1α, promoting a hypoxic response even under normoxic conditions, which can lead to changes in gene expression related to angiogenesis, cell proliferation, and glucose metabolism. This mechanism positions succinate as a crucial link between metabolic state and transcriptional regulation. Through these signaling pathways, succinate plays a critical role in cellular adaptation to nutrient stress and environmental changes, orchestrating complex cellular responses.

Regulation of Succinate Metabolism and its Epigenetic Impact

The regulation of succinate levels is multifaceted, involving both metabolic and genetic control mechanisms. The activity ofSDH, the enzyme responsible for succinate catabolism, is subject to allosteric control and post-translational modifications that fine-tune its efficiency based on cellular energy status and redox balance. Genetic mutations inSDH subunits (SDHA, SDHB, SDHC, SDHD, SDHAF2) lead to impaired enzyme function and subsequent intracellular accumulation of succinate. This accumulation is a significant regulatory event, as high succinate concentrations act as an “oncometabolite.”

Elevated succinate levels can inhibit the activity of ten-eleven translocation (TET) enzymes, which are crucial for DNA demethylation, and KDMenzymes, which remove methyl groups from histones. By inhibiting these epigenetic modifiers, succinate can induce widespread changes in DNA methylation and histone modification patterns, leading to altered gene expression. These epigenetic reprogramming events contribute to changes in cell identity, proliferation, and differentiation, profoundly impacting cellular phenotype and potentially driving disease progression.

Integrated Metabolic Networks and Succinate Crosstalk

Succinate is a key node within an intricate network of metabolic pathways, demonstrating extensive crosstalk with other metabolic routes beyond the TCA cycle. Its accumulation or depletion can significantly impact the flux through glycolysis, gluconeogenesis, fatty acid synthesis, and amino acid metabolism. For instance, succinate can influence the pyruvate dehydrogenase complex, which links glycolysis to the TCA cycle, thereby modulating the fate of glucose-derived carbon. It also plays a role in the malate-aspartate shuttle, which facilitates the transfer of reducing equivalents across the mitochondrial membrane.

This systems-level integration ensures that cellular metabolism is tightly coordinated, allowing cells to adapt efficiently to changes in nutrient availability and energy demand. The interconnectedness of succinate metabolism with other pathways underscores its role in maintaining overall cellular homeostasis and redox balance. Its influence extends to the regulation of reactive oxygen species (ROS) production, asSDH is a source of ROS, highlighting its critical involvement in cellular stress responses and signaling.

Succinate Dysregulation in Disease Pathogenesis

Dysregulation of succinate metabolism is implicated in the pathogenesis of several human diseases, particularly those involving mitochondrial dysfunction and altered cellular signaling. Genetic defects inSDHsubunits, leading to succinate accumulation, are strongly associated with hereditary paragangliomas, pheochromocytomas, and renal cell carcinoma. In these conditions, elevated succinate acts as an oncometabolite, promoting tumorigenesis throughHIF-1αstabilization and epigenetic alterations. The pseudohypoxic state induced by succinate accumulation drives changes in gene expression that support cancer cell survival and proliferation.

Beyond cancer, aberrant succinate levels are linked to metabolic disorders, neurodegenerative diseases, and inflammatory conditions. Understanding the precise mechanisms by which succinate dysregulation contributes to these pathologies offers potential avenues for therapeutic intervention. TargetingSDH activity, SUCNR1signaling, or the downstream epigenetic effects of succinate are active areas of research, aiming to restore metabolic balance and mitigate disease progression.

Clinical Relevance

Succinate, a vital intermediate in the tricarboxylic acid (TCA) cycle, is fundamental to cellular energy metabolism and mitochondrial respiration. Beyond its central role in ATP production, succinate also functions as a signaling molecule, with its levels and compartmentalization influencing gene expression, immune responses, and cellular adaptation to stress. Emerging research highlights its significance in various pathophysiological processes, underscoring its potential as a diagnostic marker, prognostic indicator, and therapeutic target in clinical practice.

Metabolic Dysregulation and Disease Pathogenesis

Perturbations in succinate metabolism are frequently observed in several disease states, providing valuable insights into their underlying mechanisms and potential for clinical management. In oncology, elevated succinate, often due to mutations in succinate dehydrogenase (SDH) or hypoxic conditions, can act as an oncometabolite. It inhibits prolyl hydroxylases, stabilizing hypoxia-inducible factors (HIFs), which promotes tumor growth, angiogenesis, and metastasis. Consequently, measuring succinate levels could serve as a prognostic indicator for predicting tumor aggressiveness, assessing disease progression, and identifying patients likely to respond to metabolism-targeting therapies, thereby supporting personalized medicine approaches in cancer care. Furthermore, dysregulated succinate metabolism is implicated in metabolic disorders such as obesity and type 2 diabetes, where it contributes to mitochondrial dysfunction and inflammatory responses, suggesting its utility in early risk stratification and guiding preventive strategies for these widespread conditions.

Inflammation, Oxidative Stress, and Organ Injury

Succinate plays a critical role in modulating inflammatory and oxidative stress pathways, making it highly relevant in various acute and chronic organ injuries and systemic inflammatory conditions. Extracellular succinate can activate the succinate receptor (GPR91), leading to the activation of immune cells, particularly macrophages, and the release of pro-inflammatory cytokines. This signaling pathway contributes to the pathogenesis of conditions like sepsis, autoimmune diseases, and ischemia-reperfusion injury in vital organs such as the heart, kidneys, and brain. Monitoring succinate concentrations could therefore offer a valuable tool for assessing disease severity, predicting the likelihood of complications, and stratifying patients at high risk for severe inflammatory responses or progressive organ damage. Understanding these mechanisms opens avenues for developing targeted therapies that modulate succinate signaling to mitigate inflammation and protect organs from injury.

Biomarker Potential and Therapeutic Targeting

The multifaceted involvement of succinate in health and disease positions it as a promising candidate for diagnostic and prognostic biomarker development, as well as a direct target for therapeutic interventions. Its measurable concentrations in biological fluids, such as blood, urine, or cerebrospinal fluid, could offer non-invasive diagnostic utility for conditions ranging from rare inborn errors of metabolism, like succinate dehydrogenase deficiency, to more prevalent diseases, including certain cancers, cardiovascular conditions, and neurodegenerative disorders. Beyond diagnosis, dynamic changes in succinate levels can serve as a monitoring strategy to track disease progression, evaluate the efficacy of existing treatments, and identify patient subgroups that may benefit most from specific pharmacological agents. Research into compounds that modulate succinate production, degradation, or receptor activation represents a significant area of therapeutic development, aiming to correct underlying metabolic imbalances and improve patient outcomes across a broad spectrum of diseases.

References

[1] Rutter, Jared, et al. “Succinate dehydrogenase: an enzyme and a tumor suppressor.”Annual Review of Biochemistry, vol. 78, 2009, pp. 625-651.

[2] Chouchani, Edward T., et al. “Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.”Nature, vol. 515, no. 7527, 2014, pp. 431-435.

[3] He, Weihong, et al. “Succinate receptor GPR91 provides a link between metabolic dysregulation and inflammation in adipose tissue.”Proceedings of the National Academy of Sciences, vol. 105, no. 48, 2008, pp. 18932-18937.