カルニチン回路異常症

Acetyl-CoA is a central metabolite that links energy status to transcriptional regulation through protein acetylation, yet its functions in skeletal biology depend strongly on subcellular compartmentalization. Because acetyl-CoA does not freely traverse biological membranes, its mitochondrial, cytosolic, and nuclear pools are maintained through compartment-specific synthesis and exchange routes, including the citrate-SLC25A1-ACLY axis, acetylcarnitine/carnitine cycling, acetate-dependent ACSS2 activity, and local nuclear enzyme activity. This review synthesizes current evidence that three conserved modules, including glycolytic/PDC-driven mitochondrial production, CIC/ACLY-mediated citrate export, and HAT-dependent acetylation, connect carbon flux with skeletal cell fate. However, lineage-specific outcomes are shaped by local acetyl-CoA availability, acetyltransferase context, and the transcription-factor landscape, including RUNX2 (osteogenesis), SOX9 (chondrogenesis) and NFATc1 (osteoclastogenesis). Critically, compartmentalized acetyl-CoA dysregulation can contribute to different pathological states: excessacetyl-CoA supply is linked to ACLY/FAO-driven cartilage catabolism and osteoclast resorption, whereas insufficient nucleocytosolic supply is associated with impaired regenerative programs in aged or inflamed bone. This duality argues for context-specific therapeutic strategies that either restrain excess acetyl-CoA flux or restore deficient pools. We propose that the translational bottleneck is not target identification but delivery precision, advocating for localized metabolite supplementation, cell-selective ACLY/FAO inhibitors, and spatial acetylome mapping to deconvolute cell-type-specific fluxes. Moving beyond broad HDAC/HAT modulation toward compartment-resolved strategies will be essential for translating acetyl-CoA biology into effective skeletal therapies.

BACKGROUND: Primary carnitine deficiency (PCD) is a rare yet treatable disorder of the carnitine cycle causing defective fatty acid oxidation. PCD presents with considerable phenotypic variability, including sudden cardiac death as the initial manifestation. CASE SUMMARY: An 18-year-old female born in India presented with a ventricular fibrillation cardiac arrest. Cardiac evaluation was notable for normal anatomy, nonspecific repolarization changes on electrocardiogram, and cardiac magnetic resonance image showing a Takotsubo-like cardiomyopathy phenotype. Genetic testing identified a homozygous pathogenic variant in SLC22A5 (c.43G>T; p.Gly15Trp) consistent with autosomal recessive PCD. Confirmatory testing demonstrated severely reduced total carnitine levels, which normalized after carnitine supplementation. DISCUSSION: PCD is a rare metabolic condition which can manifest with malignant ventricular arrhythmias. While PCD is routinely detected via the newborn metabolic screen, it should be considered in individuals with cardiac abnormalities who were born internationally. TAKE-HOME MESSAGE: This case highlights malignant ventricular arrhythmia as an initial presentation of PCD.

Neuronal metabolism fundamentally modulates synaptic activity, yet how single-cell metabolic architecture aligns with electrophysiological diversity remains elusive. By integrating patch-clamp electrophysiology with single-neuron mass spectrometry (SNMS), we resolve metabolomic heterogeneity across suprachiasmatic nucleus (SCN) neurons, revealing six metabolic states with distinct synaptic dynamics, from lipid-enriched SCN1 exhibiting high-frequency presynaptic activity to quiescent SCN6. Pathway analysis linked metabolic state-specific signatures to sulfur metabolism, glutathione regulation, and citrate cycle dynamics. Machine learning and correlation networks mapped metabolites to functional parameters: histidine, carnitine, and creatinine regulated neuronal activity, validated by intracellular metabolite delivery experiments. Strikingly, light-dark cycles dynamically reconfigured most of the metabolite-postsynaptic current correlations, including light-induced taurine coupling to synaptic transmission. This multimodal platform establishes cellular metabolism as a tunable factor associated with neuronal heterogeneity and circadian plasticity, suggesting potential therapeutic avenues for circadian disorders.

Hypertension remains a prevalent, modifiable risk factor for cardiovascular disease, with many patients failing to achieve optimal blood pressure (BP) control despite existing therapies. Pharmacometabolomics offers promise by identifying metabolic biomarkers linked to drug response and holds potential for individualizing antihypertensive treatment. We conducted a systematic review of studies from 2013 to 2023, screening 2577 articles and including five that investigated metabolomics-based biomarkers for antihypertensive drug response in cases of primary hypertension. In total, 46 metabolites were significantly associated with BP responses to diuretics, beta-blockers, and ACE inhibitors or angiotensin receptor blockers. Key predictive metabolites included arachidonic acid, sphingosine-1-phosphate, 2-oxoglutarate, and arachidonoyl-carnitine, affecting responses across fatty acid metabolism, sphingolipid metabolism, the TCA cycle, and amino acid metabolism. This review highlights the potential of pharmacometabolomics to uncover metabolites and pathways associated with individual BP response to antihypertensive drugs. Further validation in diverse populations, drug classes, and combination treatments is needed.

The urea cycle is essential for ammonia detoxification. Deficiencies in this pathway cause urea cycle disorders (UCDs), characterized by hyperammonemia and severe systemic and neurological manifestations. While ammonia toxicity is well established, the contribution of urea cycle altered amino acids that accumulate in specific UCDs to cellular stress and DNA damage-associated responses remains poorly understood. This study investigated the DNA damage effects of ornithine (1 mM), homocitrulline (0.5 mM), citrulline (1 mM), and arginine (1 mM), alone and combined with ammonia (1 mM), in human peripheral leukocytes, as well as the protective effects of N-acetylcysteine (1 mM) and L-carnitine (60 µM). DNA damage was evaluated using the comet assay and statistically analyzed. All treatments induced significant DNA damage compared with controls. When tested individually at pathophysiologically relevant concentrations, urea cycle-related metabolites produced measurable increases in DNA damage, with citrulline and arginine inducing damage comparable to ammonia. Homocitrulline also caused DNA damage, to a lesser extent, while ornithine induced the lowest levels among isolated treatments. Combined exposure to ammonia and amino acids markedly increased DNA damage levels compared with isolated conditions, emphasizing the impact of metabolic imbalance in UCDs. The highest DNA damage indices were observed with ornithine and homocitrulline in the presence of ammonia, indicating potential synergistic interactions. L-carnitine significantly reduced DNA damage in all experimental conditions. N-acetylcysteine also reduced DNA damage effects in most combinations, except for ornithine with ammonia. Overall, these findings demonstrate that both isolated and combined UCD-related metabolites are associated with increased DNA damage under hyperammonemic conditions and support antioxidant strategies as potential complementary approaches to mitigate genomic stress in UCDs.