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Spermine oxidase promotes oxidative stress during islet inflammation

ABSTRACT: Diabetes is characterized by impaired glucose homeostasis resulting from the dysfunction and loss of insulin-producing islet β cells, with oxidative stress emerging as a central contributor to β-cell injury. The polyamines (putrescine, spermidine, spermine) are known to regulate cellular stress responses, and their metabolism can generate reactive oxygen species (ROS) and reactive aldehydes through catabolic enzymes, including spermine oxidase (Smox) and polyamine oxidase (Paox). Transcriptomic analyses of mouse and human islets exposed to proinflammatory cytokines revealed induction of Smox/SMOX but no change in Paox/PAOX, suggesting a potential role for Smox in inflammation-associated oxidative stress in islets. In developing zebrafish, the smox gene is expressed in the pancreas and enriched within endocrine cells. Using a β-cell-specific ROS-inducible transgenic zebrafish model, smox knockdown reduced intra-islet ROS and macrophage recruitment. Metabolomic profiling of zebrafish embryos showed that smox deficiency did not affect spermine or spermidine levels but led to the accumulation of acetylated polyamines, consistent with the rerouting of polyamine flux through alternative acetylation pathways to ensure homeostasis of polyamine levels. RNA sequencing of zebrafish embryos demonstrated that smox deficiency induces distinct transcriptional programs, with enrichment of cell cycle and RNA processing pathways at baseline and reprogramming of stress, translational, and immune-associated pathways during injury. Mechanistically, Smox generates both hydrogen peroxide and the reactive aldehyde acrolein, whereas Paox-dependent pathways produce hydrogen peroxide without acrolein. These findings support a model in which Smox amplifies β-cell stress through aldehyde-mediated toxicity and identify polyamine catabolism as a modifiable pathway in the setting of β-cell injury.

ORGANISM(S): Danio rerio

PROVIDER: GSE328689 | GEO | 2026/07/11

REPOSITORIES: GEO

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Project description:Polyamines (putrescine, spermidine, and spermine) are major organic polycations essential for a wide spectrum of cellular processes. The cells require mechanisms to maintain homeostasis of intracellular polyamines to prevent otherwise severe adverse effects. We performed a detailed transcriptome profile analysis of P. aeruginosa in response to agmatine and putrescine with an emphasis in polyamine catabolism. Agmatine serves as precursor compound for putrescine (and hence spermidine and spermine), which was proposed to convert into GABA and succinate before entering the TCA cycle in support of cell growth as the sole source of carbon and nitrogen. Two acetylpolyamine amidohydrolases, AphA and AphB, were identified to be involved in the conversion of agmatine into putrescine. Enzymatic products of AphA were confirmed by mass spectrometry analysis. Interestingly, the alanine-pyruvate cycle was shown indispensable for polyamine utilization. The newly identified dadRAX locus, encoding the regulator, alanine transaminase and racemase respectively, coupled with SpuC, the major putrescine-pyruvate transaminase, were key components to maintain alanine homeostasis. Corresponding mutant strains were severely hampered in polyamine utilization. On the other hand, the alternative gamma-glutamylation pathway for the conversion of putrescine into GABA was also discussed. Subsequently, GabD, GabT and PA5313 were identified for GABA utilization. Growth defect of PA5313 gabT double mutant in GABA suggested the importance of these two transaminases. The succinic-semialdehyde dehydrogenase activity of GabD and its induction by GABA was also demonstrated in vitro. Polyamine utilization in general was proven independent of the PhoPQ two-component system even the expression of which was induced by polyamines. Multiple potent catabolic pathways as depicted in this study could serve pivotal roles in control of intracellular polyamine levels. Keywords: Metabolism, polyamines, agmatine, putrescine, glutamate, phoPQ.

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Spermine oxidase promotes oxidative stress during islet inflammation

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