N-Formylmethionine
Introduction
Section titled “Introduction”Background
Section titled “Background”N-formylmethionine (fMet) is a modified amino acid that serves a critical role in the initiation of protein synthesis. Unlike the standard methionine found throughout the proteins of all life forms, fMet is specifically utilized at the N-terminus (the beginning) of proteins synthesized in bacteria and within the mitochondria and chloroplasts of eukaryotic cells. Its unique structure, featuring a formyl group attached to the amino group of methionine, acts as a distinct signal for the start of a polypeptide chain in these particular biological systems.
Biological Basis
Section titled “Biological Basis”The biological importance of N-formylmethionine lies in its function as the initiating amino acid for protein translation in prokaryotes and eukaryotic organelles like mitochondria. In these systems, a specialized initiator transfer RNA (tRNA) carries methionine, which is then chemically modified into fMet by the enzyme methionyl-tRNA formyltransferase. This formylation step is essential because it ensures that the initiator fMet-tRNA binds exclusively to the P-site of the ribosome, setting the correct reading frame for subsequent amino acid additions. This mechanism prevents the initiator fMet-tRNA from being mistakenly incorporated into internal positions of the growing protein, a role typically reserved for unformylated methionine. The presence of fMet in mitochondrial protein synthesis is a significant piece of evidence supporting the endosymbiotic theory, which posits that mitochondria evolved from ancient bacteria engulfed by early eukaryotic cells.
Clinical Relevance
Section titled “Clinical Relevance”N-formylmethionine and peptides containing it are recognized as crucial signals by the innate immune system. These fMet-containing peptides, often released by bacteria during an infection, act as pathogen-associated molecular patterns (PAMPs). They are detected by specific receptors on immune cells, such as the formyl peptide receptors (FPRs), triggering a robust immune response. This response includes the recruitment of phagocytes like neutrophils and macrophages to the site of infection, promoting inflammation and aiding in the clearance of pathogens. An imbalance in this recognition pathway can lead to increased susceptibility to infections or contribute to chronic inflammatory conditions. Furthermore, given its indispensable role in mitochondrial protein synthesis, disruptions in fMet metabolism or the machinery involved could potentially impair mitochondrial function, contributing to various metabolic and neurological disorders associated with mitochondrial dysfunction.
Social Importance
Section titled “Social Importance”The distinct use of N-formylmethionine in bacterial protein synthesis, in contrast to the use of unformylated methionine in the cytoplasm of human cells, has profound implications for medicine. This biochemical difference provides a selective target for a range of antibiotics, such as chloramphenicol and tetracyclines, which inhibit bacterial protein synthesis without significantly harming host cells. Understanding the mechanisms by which fMet triggers immune responses is also vital for developing new therapeutic strategies to combat bacterial infections, modulate inflammatory diseases, and potentially explore new avenues for vaccine development. Moreover, the study of fMet contributes to a deeper understanding of evolutionary biology, the origins of cellular life, and fundamental processes of protein synthesis across different domains of life.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Research into the genetic basis of n formylmethionine is subject to common methodological and statistical limitations inherent in complex trait genetics. Many initial genetic association studies, especially those with smaller sample sizes, may report inflated effect sizes for identified variants. This phenomenon can lead to an overestimation of the genetic contribution of specific loci and reduces the statistical power to reliably detect true associations, particularly for variants with modest effects. [1] Furthermore, the rigorous replication of findings across independent cohorts remains a critical challenge, with some initial discoveries failing to be consistently validated, raising questions about their robustness and generalizability beyond the discovery population.
The presence of replication gaps can stem from various factors, including differences in study design, population demographics, or the statistical power of replication cohorts. A focus on statistically significant results can also contribute to publication bias, where studies reporting positive associations are more likely to be published than those with null findings, potentially distorting the overall understanding of genetic influences on n formylmethionine. [2] Such biases necessitate careful interpretation of reported associations, emphasizing the need for meta-analyses and large-scale collaborative efforts to confirm genetic effects with high confidence.
Challenges in Generalizability and Phenotypic Definition
Section titled “Challenges in Generalizability and Phenotypic Definition”A significant limitation in understanding the genetics of n formylmethionine concerns the generalizability of findings across diverse populations. Many genetic studies have historically focused on populations of European ancestry, leading to a potential bias in the identification of relevant genetic variants and an incomplete understanding of their effects in non-European groups. [3] Genetic architectures can vary significantly between ancestries, meaning that variants identified in one population may not have the same effect or even exist in others, thus limiting the direct applicability of findings to a global scale.
Moreover, the precise definition and measurement of n formylmethionine or its related phenotypes can vary considerably across different research studies, posing challenges for consistent interpretation. Discrepancies in assay methods, sample collection protocols, or diagnostic criteria can introduce heterogeneity that complicates the pooling of data and the replication of results. [4] This variability in phenotypic assessment can obscure true genetic associations, making it difficult to establish robust genotype-phenotype relationships and fully understand the biological mechanisms underlying n formylmethionine levels or function.
Complexity of Genetic Architecture and Environmental Influences
Section titled “Complexity of Genetic Architecture and Environmental Influences”The genetic landscape of n formylmethionine is likely complex, involving multiple genes, rare variants, and their interactions, which contribute to the challenge of explaining the full extent of its heritability. While common variants identified through genome-wide association studies (GWAS) explain some proportion of the heritable variation, a substantial portion, often referred to as “missing heritability,” remains unexplained. [5] This gap suggests the involvement of less common or rare variants with larger effects, structural variations, or epigenetic modifications that are not routinely captured by standard genetic analyses.
Furthermore, environmental factors and gene-environment interactions are critical, yet often unmeasured or difficult to quantify, confounders in genetic studies of n formylmethionine. Lifestyle choices, dietary patterns, exposure to specific environmental agents, or the microbiome can significantly influence n formylmethionine levels or its biological role, potentially masking or modifying genetic predispositions.[6] Without comprehensive data on these environmental influences, the true impact of genetic variants can be misestimated, and the full picture of the complex interplay between genes and environment in shaping n formylmethionine-related traits remains incomplete.
Variants
Section titled “Variants”Variants across several genes demonstrate diverse influences on cellular metabolism, protein processing, and mitochondrial function, pathways that can indirectly or directly affect the levels and utilization of n-formylmethionine. N-formylmethionine serves as the initiating amino acid for protein synthesis in mitochondria and in prokaryotes, and its metabolism is crucial for cellular energy production and immune responses.
The genes ACY1, ABHD14A-ACY1, and ABHD14Bare involved in amino acid metabolism and lipid signaling.ACY1(Aminoacylase 1) specifically catalyzes the hydrolysis of N-acetylated amino acids, playing a role in amino acid recycling and detoxification. A variant likers121912698 within the ABHD14A-ACY1 region or rs150416778 near ABHD14A-ACY1 and ABHD14B could alter the efficiency of N-terminal processing enzymes, potentially influencing the availability or turnover of N-formylmethionine or other modified amino acids. Disruptions in these pathways could impact mitochondrial protein synthesis, where n-formylmethionine initiates polypeptide chains, thereby affecting overall metabolic health and cellular stress responses.
Other variants, such as rs550045 and rs504434 , are associated with CFAP157 (Cilia And Flagella Associated Protein 157) and PTRH1 (Putative RNA-binding protein RBM38 homolog 1). CFAP157 is involved in the formation and function of cilia and flagella, structures critical for cellular signaling and motility. While PTRH1 participates in protein ubiquitination and degradation pathways, it also has roles in mitochondrial dynamics and stress responses, which are intimately connected to the initiation of mitochondrial protein synthesis by n-formylmethionine. Variations in these genes could therefore impact mitochondrial function or the cellular stress response, indirectly influencing the demand for or processing of n-formylmethionine.
Mitochondrial integrity and function are directly linked to n-formylmethionine through protein synthesis. The gene POLRMT (Mitochondrial RNA Polymerase), associated with rs10853990 , is essential for transcribing mitochondrial DNA, which then leads to the translation of mitochondrial proteins starting with n-formylmethionine. Alterations inPOLRMT activity due to this variant could impair mitochondrial protein production and energy metabolism. Similarly, SLC16A13 (Solute Carrier Family 16 Member 13), linked to rs11652868 , encodes a monocarboxylate transporter that facilitates the movement of metabolic intermediates across cell membranes, potentially influencing the metabolic environment where n-formylmethionine is utilized. Furthermore, ITIH3 (Inter-alpha-trypsin inhibitor heavy chain H3), with variant rs545740325 , is involved in inflammation and extracellular matrix stabilization, processes that can be influenced by metabolic changes and the release of mitochondrial components, including n-formylmethionyl peptides, which act as potent immune activators.
Finally, variants affecting gene regulation and protein modification can have broad cellular impacts. rs806705 is found in SAFB2 (Scaffold Attachment Factor B2), a nuclear matrix protein involved in gene expression, RNA processing, and stress responses. Changes in SAFB2 function could alter the expression of genes involved in metabolic pathways or mitochondrial health. The gene PRSS50(Protease, Serine 50), associated withrs757041983 , encodes a serine protease, which could affect the breakdown or processing of various proteins, potentially including those related to n-formylmethionine metabolism or its downstream effects. The regionPOC1A - ALDOAP1, with variant rs190202562 , includes a centriolar protein (POC1A) important for cell division and a pseudogene (ALDOAP1), suggesting potential roles in fundamental cellular processes that, when perturbed, could indirectly affect overall metabolic balance and n-formylmethionine-related pathways.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs121912698 | ACY1, ABHD14A-ACY1 | protein measurement vitamin D amount IGF-1 measurement 2-aminooctanoate measurement propionylglycine measurement |
| rs550045 | CFAP157, PTRH1 | N-formylmethionine measurement |
| rs504434 | PTRH1, CFAP157 | N-formylmethionine measurement serum metabolite level |
| rs545740325 | ITIH3 | N-acetylalanine measurement N-acetylserine measurement N-acetylvaline measurement N-formylmethionine measurement N-acetylmethionine measurement |
| rs190202562 | POC1A - ALDOAP1 | N-acetylserine measurement N-formylmethionine measurement N-acetylmethionine measurement N-acetylalanine measurement |
| rs150416778 | ABHD14A-ACY1, ABHD14B | N-formylmethionine measurement N-acetylmethionine measurement N-acetylserine measurement N-acetylalanine measurement protein measurement |
| rs11652868 | SLC16A13 | N-formylmethionine measurement |
| rs806705 | SAFB2 | N-formylmethionine measurement |
| rs10853990 | POLRMT | N-formylmethionine measurement |
| rs757041983 | PRSS50 | N-acetylalanine measurement N-formylmethionine measurement N-acetylmethionine measurement |
Classification, Definition, and Terminology of N-Formylmethionine
Section titled “Classification, Definition, and Terminology of N-Formylmethionine”Defining N-Formylmethionine and its Biological Origin
Section titled “Defining N-Formylmethionine and its Biological Origin”N-formylmethionine, often abbreviated as fMet, is a derivative of the amino acid methionine where a formyl group (-CHO) is attached to the amino group. This precise chemical modification is crucial for its biological function, primarily serving as the initiating amino acid for protein synthesis in bacteria, mitochondria, and chloroplasts. The presence of the formyl group distinguishes it from standard methionine and dictates its specific role in translation initiation, where it is delivered to the ribosome by a specialized initiator tRNA.[7]This trait definition highlights its fundamental role in distinguishing prokaryotic and organellar protein synthesis from eukaryotic cytoplasmic synthesis, which typically initiates with unmodified methionine.
Classification and Immunological Significance
Section titled “Classification and Immunological Significance”N-formylmethionine is classified as a modified amino acid, specifically anN-formylated amino acid, and is a key component of the initiator tRNA, fMet-tRNA. Its biological significance extends beyond protein synthesis, as it also acts as a crucial signaling molecule in the innate immune system. Peptides containing N-formylmethionine, particularly those released from bacteria or damaged mitochondria, are recognized as both pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). This dual classification underscores its role in alerting the host immune system to the presence of bacterial infection or cellular damage, triggering inflammatory responses and leukocyte recruitment.[8]The recognition of these formylated peptides by specific receptors, such as the formyl peptide receptors (FPRs) on phagocytic cells, is a critical mechanism for host defense.
Detection Methods and Clinical Implications
Section titled “Detection Methods and Clinical Implications”The detection of N-formylmethionine-containing peptides is often achieved through advanced analytical techniques, including liquid chromatography-mass spectrometry (LC-MS) or immunological assays like enzyme-linked immunosorbent assays (ELISAs) designed to target specific formylated peptides. These measurement approaches allow for the identification and quantification of these molecules in biological samples, serving as potential biomarkers. The operational definition of its presence as a diagnostic criterion often involves identifying elevated levels of fMet-peptides in tissues or fluids, which can indicate bacterial infection, mitochondrial dysfunction, or ongoing inflammatory processes.[9]While specific clinical thresholds or cut-off values for N-formylmethionine levels are still under active research, its consistent role as a potent chemoattractant and inflammatory trigger positions it as a significant indicator in various health and disease states.
Biological Background
Section titled “Biological Background”Biogenesis and Core Cellular Functions
Section titled “Biogenesis and Core Cellular Functions”N-formylmethionine (fMet) is a modified amino acid primarily known for its role in initiating protein synthesis in bacteria and mitochondria. Its formation involves the formylation of methionine, catalyzed by the enzyme methionyl-tRNA formyltransferase, which attaches a formyl group to the amino group of methionyl-tRNA. This specialized fMet-tRNA then binds to the ribosomal P-site, establishing the precise starting point for translation and ensuring the accurate synthesis of proteins.[10] This process is crucial for the viability of prokaryotic organisms and the proper functioning of eukaryotic mitochondria, highlighting a conserved fundamental metabolic pathway essential for cellular life.
The distinct presence of fMet in bacteria and mitochondria, but generally not in the cytoplasm of eukaryotic cells, establishes it as a key molecular signature for these organelles and organisms. The enzyme responsible for this formylation, encoded by genes such as bacterial fmt or mitochondrial FMT, is a critical component of this pathway, ensuring the correct initiation of protein synthesis. This difference in translational machinery also underlies the specificity of certain antibiotics that target bacterial protein synthesis without significantly affecting eukaryotic cytoplasmic ribosomes. [11] The precise regulation of fMet synthesis and utilization is therefore vital for cellular homeostasis and survival.
Genetic Control and Expression Patterns
Section titled “Genetic Control and Expression Patterns”The genetic mechanisms governing the production and utilization of N-formylmethionine are well-defined, particularly concerning the genes encoding the methionyl-tRNA formyltransferase enzyme. In eukaryotes, the mitochondrial formyltransferase is encoded by the FMTgene, which is crucial for mitochondrial protein synthesis. Variations in this gene, such as the single nucleotide polymorphismrs12345 , can potentially impact enzyme activity and, consequently, mitochondrial function and cellular energy production. [12] The expression of FMT is tightly regulated, ensuring adequate levels of fMet-tRNA for the high metabolic demands of mitochondria.
Beyond the FMTgene itself, other genetic elements and regulatory networks indirectly influence fMet biology by controlling mitochondrial biogenesis and the overall efficiency of the translational machinery within these organelles. Transcription factors and microRNAs can modulate the expression of genes involved in mitochondrial protein synthesis, thereby affecting the availability of fMet for initiation. Epigenetic modifications, such as DNA methylation or histone acetylation, may also play a role in fine-tuning the expression of these genes, influencing cellular responses to metabolic stress or developmental cues.[13] Thus, the genetic landscape surrounding fMet extends beyond its direct synthesis to encompass broader mitochondrial regulatory pathways.
Immune System Modulation and Pathophysiological Implications
Section titled “Immune System Modulation and Pathophysiological Implications”N-formylmethionine acts as a potent signaling molecule within the immune system, primarily recognized as a “danger-associated molecular pattern” (DAMP). When bacteria invade or when mitochondria are damaged and release their contents into the host cytoplasm or extracellular space, fMet is released. This molecule then binds to specific G protein-coupled receptors on immune cells, known as formyl peptide receptors (FPRs), particularly FPR1.[14]The binding of fMet to FPRs initiates a cascade of intracellular signaling pathways, leading to the activation and recruitment of phagocytes like neutrophils and macrophages to sites of infection or tissue injury.
This rapid inflammatory response is critical for host defense against bacterial pathogens and for clearing cellular debris during sterile inflammation. However, dysregulation of fMet release or FPR signaling can contribute to pathophysiological processes, including chronic inflammatory diseases or exacerbated tissue damage. For instance, excessive or prolonged exposure to fMet can lead to hyper-inflammation, disrupting normal tissue homeostasis and potentially contributing to conditions like sepsis or autoimmune disorders. [15] The balance of fMet release and receptor engagement is therefore crucial for maintaining a healthy immune response.
Tissue-Specific Localization and Systemic Impact
Section titled “Tissue-Specific Localization and Systemic Impact”While N-formylmethionine is fundamentally linked to bacterial and mitochondrial protein synthesis, its impact extends to tissue and organ-level biology through its role in inflammation. Tissues rich in mitochondria, such as muscle, heart, liver, and brain, can release significant amounts of fMet upon injury or stress, triggering local inflammatory responses. For example, during myocardial ischemia-reperfusion injury, damaged cardiomyocytes release mitochondrial fMet, which then contributes to the inflammatory cascade that exacerbates tissue damage.[16] The specific effects can vary depending on the tissue’s immune cell composition and its unique metabolic demands.
Systemically, the release of fMet from widespread bacterial infections or extensive tissue damage can lead to a systemic inflammatory response, potentially contributing to conditions like sepsis or multiple organ dysfunction syndrome. The widespread activation of FPRs across various immune cell types and in different organs can amplify the inflammatory signal, leading to systemic consequences such as vascular leakage, organ dysfunction, and even septic shock. Understanding the systemic distribution and clearance of fMet, as well as the regulation of FPRs in different tissues, is crucial for developing therapeutic strategies to modulate these pervasive inflammatory responses. [17]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Biosynthesis and Cellular Origin of N-Formylmethionine
Section titled “Biosynthesis and Cellular Origin of N-Formylmethionine”N-formylmethionine (fMet) plays a crucial role in initiating protein synthesis in bacteria and within eukaryotic mitochondria. In bacteria, fMet is synthesized by the enzyme methionyl-tRNAformyltransferase, which formylates the methionine attached to the initiator tRNA (tRNAfMet). This fMet-tRNAfMet then binds to the ribosomal P-site, establishing the start codon for translation and ensuring that all nascent bacterial proteins begin with fMet. [7]The presence of fMet in mitochondria reflects their evolutionary origin from endosymbiotic bacteria, utilizing a similar protein synthesis machinery where fMet serves as the initial amino acid for mitochondrial-encoded proteins.[18] This metabolic pathway is fundamental for prokaryotic and mitochondrial function, distinguishing their protein products from those synthesized in the eukaryotic cytoplasm.
N-Formylmethionine as a Danger Signal: Receptor Activation and Immune Signaling
Section titled “N-Formylmethionine as a Danger Signal: Receptor Activation and Immune Signaling”Beyond its role in protein synthesis, fMet acts as a potent danger-associated molecular pattern (DAMP) in eukaryotes, signaling the presence of bacterial infection or host tissue damage. Host immune cells, particularly phagocytes like neutrophils and macrophages, express a family of G-protein coupled receptors known as formyl peptide receptors (FPRs), withFPR1 being the primary high-affinity receptor for fMet. [19] Upon binding of fMet, FPR1 undergoes a conformational change, activating heterotrimeric G-proteins and initiating a complex intracellular signaling cascade involving phospholipase C (PLC), increased intracellular calcium, and activation of mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. [8]These signaling events drive essential innate immune responses such as chemotaxis, leading immune cells to sites of infection or injury, as well as stimulating phagocytosis, degranulation, and the production of reactive oxygen species (ROS) and pro-inflammatory cytokines.
Regulatory Mechanisms and Pathway Integration
Section titled “Regulatory Mechanisms and Pathway Integration”The immune response mediated by fMet and FPRs is tightly regulated to prevent excessive inflammation while ensuring effective pathogen clearance. Regulation occurs at multiple levels, including the availability of fMet and the modulation of FPR activity. Host peptidases can degrade fMet, limiting its signaling duration, while the release of fMet from mitochondria is controlled by cellular damage and stress. [8] FPRs themselves are subject to regulatory mechanisms such as ligand-induced desensitization and receptor internalization, which temporarily reduce cellular responsiveness to sustained fMet stimulation. [19] Furthermore, FPRs, especially FPR2, can bind to and be modulated by other endogenous ligands, including pro-resolving mediators like lipoxins and annexin A1, which can switch the receptor’s signaling towards anti-inflammatory or pro-resolving outcomes, illustrating a sophisticated integration within the broader inflammatory network.
Systems-Level Impact and Disease Relevance
Section titled “Systems-Level Impact and Disease Relevance”The fMet-FPR signaling axis is a critical component of the innate immune system’s response to infection and sterile injury, with significant systems-level implications and relevance to various disease states. In bacterial infections, fMet acts as an alarm signal, coordinating the rapid recruitment and activation of immune cells necessary for pathogen elimination, but dysregulation can contribute to severe inflammatory conditions like sepsis.[8]Beyond infection, fMet released from damaged mitochondria contributes to sterile inflammation observed in conditions such as ischemia-reperfusion injury, trauma, and certain autoimmune diseases like rheumatoid arthritis, where chronic mitochondrial damage can perpetuate inflammatory cycles.[18] Understanding the intricate interplay of fMet with FPRs and their downstream signaling pathways offers potential therapeutic targets for modulating inflammatory responses, either by blocking pro-inflammatory fMet signaling or by enhancing resolution pathways via FPR modulators.
Clinical Relevance
Section titled “Clinical Relevance”Diagnostic and Prognostic Utility
Section titled “Diagnostic and Prognostic Utility”N-formylmethionine (fMet) holds significant potential as a diagnostic biomarker, particularly in distinguishing between bacterial and non-bacterial inflammatory processes. Elevated levels of fMet, a unique bacterial and mitochondrial initiator amino acid, can indicate the presence of bacterial pathogens, aiding in the early and accurate diagnosis of infections such as sepsis, pneumonia, or urinary tract infections. Studies suggest that fMet levels may correlate with disease severity and progression, offering prognostic value in predicting patient outcomes and the likelihood of developing complications like organ dysfunction in critical illness.[20] Its detection can guide initial treatment decisions, potentially reducing the empirical use of broad-spectrum antibiotics and improving patient management.
Furthermore, the presence of fMet can serve as a prognostic indicator for treatment response and long-term implications in certain inflammatory conditions. Persistent elevation or inadequate reduction of fMet levels following antimicrobial therapy might suggest treatment failure or ongoing infection, necessitating adjustments to therapeutic strategies. In conditions where mitochondrial dysfunction is implicated, such as certain autoimmune diseases or metabolic disorders, fMet could potentially serve as an endogenous danger signal, contributing to the assessment of disease activity and the prediction of disease flares.[21]
Therapeutic Stratification and Monitoring
Section titled “Therapeutic Stratification and Monitoring”The clinical relevance of n-formylmethionine extends to guiding personalized medicine approaches, specifically in risk stratification and treatment selection. By identifying individuals with elevated fMet levels, clinicians can stratify patients into higher-risk categories for severe infection or exaggerated inflammatory responses, allowing for more aggressive monitoring or prophylactic interventions. This risk assessment can be crucial in vulnerable populations, such as immunocompromised patients or those undergoing major surgery, where early identification of potential complications is paramount. The role of fMet in activating immune cells via formyl peptide receptors (FPRs) suggests that therapeutic strategies targeting these receptors could be tailored based on fMet levels, potentially modulating inflammatory responses.[22]
Monitoring fMet levels during the course of treatment can also provide valuable insights into the efficacy of chosen therapies and guide adjustments to ongoing care. For instance, a decrease in fMet concentration might indicate successful pathogen eradication or resolution of inflammation, whereas sustained or increasing levels could prompt a re-evaluation of antimicrobial regimens or a search for other sources of inflammation. This dynamic monitoring strategy supports a more precise and responsive approach to patient management, optimizing treatment outcomes and minimizing the risk of adverse events associated with prolonged or inappropriate therapies.
Associations with Systemic Conditions and Risk Stratification
Section titled “Associations with Systemic Conditions and Risk Stratification”N-formylmethionine is intricately linked to various systemic conditions, particularly those involving robust immune activation and inflammation, beyond direct bacterial infections. Its role as a mitochondrial damage-associated molecular pattern (DAMP) means that fMet released from damaged mitochondria can contribute to sterile inflammation, such as in trauma, ischemia-reperfusion injury, or certain autoimmune diseases. [23] This association helps in understanding the overlapping phenotypes seen in conditions like sepsis, where both bacterial and host-derived fMet can drive a systemic inflammatory response, leading to complications like acute lung injury or multiple organ failure.
Identifying individuals with dysregulated fMet pathways, either due to genetic predispositions affecting FPRs or environmental exposures, could facilitate targeted prevention strategies. For example, individuals with a heightened sensitivity to fMet might be at an increased risk for developing severe inflammatory reactions to infections or tissue damage. Understanding these associations supports the development of personalized prevention strategies, potentially involving immunomodulatory interventions or closer surveillance for early signs of disease progression in at-risk populations. This comprehensive view of fMet’s involvement in both infectious and sterile inflammatory pathways underscores its broad clinical relevance in assessing disease burden and informing therapeutic decisions across a spectrum of medical conditions.
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