@article{parizkova_l-glutamine_2026,
	title = {L-{Glutamine} {Modulates} {Root} {Architecture} and {Hormonal} {Balance} in {Arabidopsis}},
	volume = {178},
	copyright = {© 2025 The Author(s). Physiologia Plantarum published by John Wiley \& Sons Ltd on behalf of Scandinavian Plant Physiology Society.},
	issn = {1399-3054},
	url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/ppl.70723},
	doi = {10.1111/ppl.70723},
	abstract = {Nitrogen (N) availability is a key determinant of plant growth and development. Here, we investigate how different N sources shape Arabidopsis thaliana root system architecture, metabolism and hormone dynamics. L-glutamine (L-GLN) significantly enhances root biomass compared to nitrate (KNO3) without compromising shoot growth. This effect emerges after 2 weeks and is independent of L-GLN's role as a carbon or ammonium source or of potential L-GLN-induced pH changes due to ammonium release, indicating a specific function of L-GLN as a N source and signaling molecule. A reverse genetic screen identified AMINO ACID PERMEASE 1 (AAP1)-mediated uptake and GLUTAMINE SYNTHETASE (GS)-dependent assimilation as essential for L-GLN-induced root biomass. In contrast, the N-sensing regulators NITRATE TRANSPORTER 1.1 (NRT1.1) and AMMONIUM TRANSPORTER (AMT) family members contribute to the differential root responses between KNO3 and L-GLN. Metabolic profiling revealed distinct amino acid signatures under these N sources, irrespective of genotype. Hormonal analyses showed that L-GLN modulates auxin homeostasis, with auxin supplementation restoring primary root growth and lateral root symmetry under L-GLN conditions. L-GLN also reconfigures cytokinin balance by elevating cZ while reducing tZ, collectively shaping root system architecture through hormone-dependent regulation. Together, these findings establish L-GLN as an integrator of N metabolism and hormone signaling in root development, highlighting its signaling capacity beyond nutrient supply and offering new perspectives for improving N use efficiency.},
	language = {en},
	number = {1},
	urldate = {2026-01-09},
	journal = {Physiologia Plantarum},
	author = {Pařízková, Barbora and Johansson, Annika I. and Juvany, Marta and Šimura, Jan and Ljung, Karin and Antoniadi, Ioanna},
	year = {2026},
	note = {\_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ppl.70723},
	keywords = {KNO3, L-GLN, auxin, cytokinin, organic N, root growth, root system architecture},
	pages = {e70723},
}

Nitrogen (N) availability is a key determinant of plant growth and development. Here, we investigate how different N sources shape Arabidopsis thaliana root system architecture, metabolism and hormone dynamics. L-glutamine (L-GLN) significantly enhances root biomass compared to nitrate (KNO3) without compromising shoot growth. This effect emerges after 2 weeks and is independent of L-GLN's role as a carbon or ammonium source or of potential L-GLN-induced pH changes due to ammonium release, indicating a specific function of L-GLN as a N source and signaling molecule. A reverse genetic screen identified AMINO ACID PERMEASE 1 (AAP1)-mediated uptake and GLUTAMINE SYNTHETASE (GS)-dependent assimilation as essential for L-GLN-induced root biomass. In contrast, the N-sensing regulators NITRATE TRANSPORTER 1.1 (NRT1.1) and AMMONIUM TRANSPORTER (AMT) family members contribute to the differential root responses between KNO3 and L-GLN. Metabolic profiling revealed distinct amino acid signatures under these N sources, irrespective of genotype. Hormonal analyses showed that L-GLN modulates auxin homeostasis, with auxin supplementation restoring primary root growth and lateral root symmetry under L-GLN conditions. L-GLN also reconfigures cytokinin balance by elevating cZ while reducing tZ, collectively shaping root system architecture through hormone-dependent regulation. Together, these findings establish L-GLN as an integrator of N metabolism and hormone signaling in root development, highlighting its signaling capacity beyond nutrient supply and offering new perspectives for improving N use efficiency.

@article{marciano_comparative_2026,
	title = {A {Comparative} {Analysis} of {Receptor}-{Like} {Kinases} in {Chlorophyta} {Reveals} the {Presence} of {Putative} {Cell} {Wall} {Integrity} {Sensors}},
	volume = {178},
	copyright = {© 2025 The Author(s). Physiologia Plantarum published by John Wiley \& Sons Ltd on behalf of Scandinavian Plant Physiology Society.},
	issn = {1399-3054},
	url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/ppl.70703},
	doi = {10.1111/ppl.70703},
	abstract = {Receptor-like kinases (RLKs) detect external and internal signals, triggering responses essential for growth and adaptation. Among internal cues, cell wall integrity (CWI) sensing plays a key role, as changes in cell wall structure activate responses critical for development and defense. While RLKs are well-studied in vascular plants, their diversity and function remain largely unknown in green algae belonging to the Chlorophyta phylum, a group that is relevant for global oxygen production and carbon cycling. Due to their varied cell wall structures, Chlorophyta offer a useful system to study the origins of CWI sensing. In this study, we used advanced bioinformatics and AI-based tools to analyze RLKs in 34 Chlorophyta species, mapping their distribution, structural features, and similarity to plant RLKs. We identified 736 putative RLKs, expanding the known repertoire in green algae. Structural analyses showed a wide range of extracellular domains, including motifs related to plant CWI sensors: domains mediating protein interactions (e.g., Leucine Rich Repeats—LRR, Plasminogen Apple Nematod e-PAN, Armadillo repeat—ARM), cell wall remodeling (e.g., glycosyl hydrolases, lyases), and mechanosensing (e.g., Leucine-Proline-X-Threonine-Glycine motifs—LPXTG, Fibronectin). This diversity suggests that mechanisms for extracellular sensing and CWI monitoring emerged early in evolution. The results provide a basis for future studies on the function of RLKs in algae and their evolutionary links to vascular plant signaling.},
	language = {en},
	number = {1},
	urldate = {2026-01-09},
	journal = {Physiologia Plantarum},
	author = {Marcianò, Demetrio and Dauphin, Bastien G. and Basso, Fabian and Funk, Christiane and Bacete, Laura},
	year = {2026},
	note = {\_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ppl.70703},
	keywords = {Chlorella vulgaris, algae-plants evolutionary conservation, microalgae signal transduction, receptor functional divergence},
	pages = {e70703},
}

Receptor-like kinases (RLKs) detect external and internal signals, triggering responses essential for growth and adaptation. Among internal cues, cell wall integrity (CWI) sensing plays a key role, as changes in cell wall structure activate responses critical for development and defense. While RLKs are well-studied in vascular plants, their diversity and function remain largely unknown in green algae belonging to the Chlorophyta phylum, a group that is relevant for global oxygen production and carbon cycling. Due to their varied cell wall structures, Chlorophyta offer a useful system to study the origins of CWI sensing. In this study, we used advanced bioinformatics and AI-based tools to analyze RLKs in 34 Chlorophyta species, mapping their distribution, structural features, and similarity to plant RLKs. We identified 736 putative RLKs, expanding the known repertoire in green algae. Structural analyses showed a wide range of extracellular domains, including motifs related to plant CWI sensors: domains mediating protein interactions (e.g., Leucine Rich Repeats—LRR, Plasminogen Apple Nematod e-PAN, Armadillo repeat—ARM), cell wall remodeling (e.g., glycosyl hydrolases, lyases), and mechanosensing (e.g., Leucine-Proline-X-Threonine-Glycine motifs—LPXTG, Fibronectin). This diversity suggests that mechanisms for extracellular sensing and CWI monitoring emerged early in evolution. The results provide a basis for future studies on the function of RLKs in algae and their evolutionary links to vascular plant signaling.

@article{ma_pangenome_2026,
	title = {A pangenome insight into the genome divergence and flower color diversity among {Rhododendron} species},
	issn = {1471-2164},
	url = {https://doi.org/10.1186/s12864-025-12461-5},
	doi = {10.1186/s12864-025-12461-5},
	abstract = {The Rhododendron genus (Rhododendron L.), recognized as the most extensive woody plant genus in the Northern Hemisphere, captivates with its strikingly beautiful corollas and variety of flower colors. In addition, the Rhododendron genus exhibits a complex evolutionary history and substantial species diversification. To comprehensively understand the genomic complexity and flower color diversity within this genus, comparative genomics has emerged as a promising approach, enabling analysis at a super-species level.},
	language = {en},
	urldate = {2026-01-09},
	journal = {BMC Genomics},
	author = {Ma, Hai-Yao and Nie, Shuai and Liu, Hai-Bo and Shi, Tian-Le and Zhao, Shi-Wei and Chen, Zhao-Yang and Bao, Yu-Tao and Li, Zhi-Chao and Mao, Jian-Feng},
	month = jan,
	year = {2026},
	keywords = {Flower color, Gene duplication, Gene loss, Rhododendron, Transposable element},
}

The Rhododendron genus (Rhododendron L.), recognized as the most extensive woody plant genus in the Northern Hemisphere, captivates with its strikingly beautiful corollas and variety of flower colors. In addition, the Rhododendron genus exhibits a complex evolutionary history and substantial species diversification. To comprehensively understand the genomic complexity and flower color diversity within this genus, comparative genomics has emerged as a promising approach, enabling analysis at a super-species level.

@article{chanwala_functions_2026,
	title = {The functions of long noncoding {RNAs} in plants},
	volume = {89},
	issn = {1369-5266},
	url = {https://www.sciencedirect.com/science/article/pii/S136952662500144X},
	doi = {10.1016/j.pbi.2025.102830},
	abstract = {Noncoding RNAs are emerging as major regulators in plant development and environmental response. MicroRNAs, small RNAs, and ribosomal RNAs have established mechanisms for generation, maturation, and function. However, long noncoding RNAs (lncRNAs) currently lack a robust classification according to their function. lncRNAs are here defined as noncoding RNAs that are longer than 200 nucleotides and generally transcribed by RNA polymerase II. They often exhibit low expression and limited sequence conservation yet display tissue or stress-specific regulation. Furthermore, lncRNAs are categorized based on their location relative to nearby genes, including sense (overlapping a gene on the same strand), antisense (overlapping on the opposite strand), intronic (located within intron), intergenic (found between genes), and bidirectional (transcribed in the opposite direction from a nearby gene). Here, we summarized the last years of work in the field of lncRNA, but instead of grouping them into the biological processes they are involved in, we attempt to group them into general functions in plants. This will not be an exhaustive grouping of known functions for lncRNA, rather a list of established functions with several characterized cases.},
	urldate = {2025-12-18},
	journal = {Current Opinion in Plant Biology},
	author = {Chanwala, Jeky and Rosenkranz, Isabell and Kindgren, Peter},
	month = feb,
	year = {2026},
	pages = {102830},
}

Noncoding RNAs are emerging as major regulators in plant development and environmental response. MicroRNAs, small RNAs, and ribosomal RNAs have established mechanisms for generation, maturation, and function. However, long noncoding RNAs (lncRNAs) currently lack a robust classification according to their function. lncRNAs are here defined as noncoding RNAs that are longer than 200 nucleotides and generally transcribed by RNA polymerase II. They often exhibit low expression and limited sequence conservation yet display tissue or stress-specific regulation. Furthermore, lncRNAs are categorized based on their location relative to nearby genes, including sense (overlapping a gene on the same strand), antisense (overlapping on the opposite strand), intronic (located within intron), intergenic (found between genes), and bidirectional (transcribed in the opposite direction from a nearby gene). Here, we summarized the last years of work in the field of lncRNA, but instead of grouping them into the biological processes they are involved in, we attempt to group them into general functions in plants. This will not be an exhaustive grouping of known functions for lncRNA, rather a list of established functions with several characterized cases.

@article{vergara_isoformmapper_2026,
	title = {{IsoformMapper}: a web application for protein-level comparison of splice variants through structural community analysis},
	volume = {32},
	issn = {1355-8382, 1469-9001},
	shorttitle = {{IsoformMapper}},
	url = {http://rnajournal.cshlp.org/content/32/1/1},
	doi = {10.1261/rna.080738.125},
	abstract = {Alternative splicing (AS) enables cells to produce multiple protein isoforms from single genes, fine-tuning protein function across numerous cellular processes. However, despite its biological importance, researchers lack effective tools to compare the domain composition of AS-derived protein isoforms because such comparisons require both structural data and specialized methods. Recent advances in AI-driven protein structure prediction, particularly AlphaFold2, now make accurate structural determination of splicing isoforms accessible, enabling functional AS analysis at the protein structure level. Here, we present IsoformMapper, a web resource that analyzes AS through network community analysis of protein structures. This approach captures 3D physical interactions between protein regions often missed by traditional domain analysis, enabling structural comparisons of isoforms across any biological system. We illustrate our tool by analyzing validated human Bcl-X protein isoforms, revealing how AS creates distinct community structures with antagonistic functional roles. As a proof of concept, we apply our tool to investigate how GENOMES UNCOUPLED1 (GUN1)–dependent retrograde signaling regulates plant de-etiolation through alternative splicing in Arabidopsis. In response to light, gun1 shows alterations in spliceosome component expression, suggesting that GUN1 contributes to AS regulation of genes essential for photosynthetic establishment. The gun1 mutant displays altered splice variant ratios for PNSL2, CHAOS, and SIG5. Our tool reveals that these isoforms form distinct protein community structures, demonstrating how AS impacts protein function and validating IsoformMapper's practical value.},
	language = {en},
	number = {1},
	urldate = {2025-12-18},
	journal = {RNA},
	author = {Vergara, Alexander and Hernández-Verdeja, Tamara and Ojeda-May, Pedro and Ramirez, Leonor and Edler, Daniel and Rosvall, Martin and Strand, Åsa},
	month = jan,
	year = {2026},
	pmid = {41136341},
	note = {Company: Cold Spring Harbor Laboratory Press
Distributor: Cold Spring Harbor Laboratory Press
Institution: Cold Spring Harbor Laboratory Press
Label: Cold Spring Harbor Laboratory Press
Publisher: Cold Spring Harbor Lab},
	keywords = {alternative splicing, plastid retrograde signaling},
	pages = {1--20},
}

Alternative splicing (AS) enables cells to produce multiple protein isoforms from single genes, fine-tuning protein function across numerous cellular processes. However, despite its biological importance, researchers lack effective tools to compare the domain composition of AS-derived protein isoforms because such comparisons require both structural data and specialized methods. Recent advances in AI-driven protein structure prediction, particularly AlphaFold2, now make accurate structural determination of splicing isoforms accessible, enabling functional AS analysis at the protein structure level. Here, we present IsoformMapper, a web resource that analyzes AS through network community analysis of protein structures. This approach captures 3D physical interactions between protein regions often missed by traditional domain analysis, enabling structural comparisons of isoforms across any biological system. We illustrate our tool by analyzing validated human Bcl-X protein isoforms, revealing how AS creates distinct community structures with antagonistic functional roles. As a proof of concept, we apply our tool to investigate how GENOMES UNCOUPLED1 (GUN1)–dependent retrograde signaling regulates plant de-etiolation through alternative splicing in Arabidopsis. In response to light, gun1 shows alterations in spliceosome component expression, suggesting that GUN1 contributes to AS regulation of genes essential for photosynthetic establishment. The gun1 mutant displays altered splice variant ratios for PNSL2, CHAOS, and SIG5. Our tool reveals that these isoforms form distinct protein community structures, demonstrating how AS impacts protein function and validating IsoformMapper's practical value.

@article{skalicky_illuminating_2026,
	title = {Illuminating the subcellular maze: fluorescence-activated organelle sorting in plant sciences},
	volume = {77},
	issn = {0022-0957},
	shorttitle = {Illuminating the subcellular maze},
	url = {https://doi.org/10.1093/jxb/eraf490},
	doi = {10.1093/jxb/eraf490},
	abstract = {The isolation of organelles is critical for gaining a deeper understanding of their functions in intracellular processes, not only at the cellular but also at the multicellular, organ, and organism levels. Isolating them into pure fractions allows for the reduction of sample complexity, thereby ensuring high quality downstream analysis, such as in protein localization studies. Since the mid-20th century, new methods of subcellular fractionation have constantly emerged. Conventional fractionation approaches based on (ultra)centrifugation typically focus on isolating only one type of organelle. Moreover, their resolving power may be inadequate for improving the limit of detection of downstream applications. Fluorescence-activated organelle sorting (FAOS) is a versatile and advanced technique that is gaining popularity due to its high efficiency. This efficiency refers to the ability to monitor organelle isolation live and to sort multiple organelle populations simultaneously from a single sample. This review offers an overview of the usage of FAOS and highlights its promising prospects within the realm of plant sciences. FAOS shows great potential for applications in both the functional and structural analysis of plant organelles while serving as a valuable isolation tool for downstream applications, including ‘omics’ studies.},
	number = {1},
	urldate = {2025-12-18},
	journal = {Journal of Experimental Botany},
	author = {Skalický, Vladimír and Antoniadi, Ioanna and Ljung, Karin and Novák, Ondřej},
	month = jan,
	year = {2026},
	pages = {120--133},
}

The isolation of organelles is critical for gaining a deeper understanding of their functions in intracellular processes, not only at the cellular but also at the multicellular, organ, and organism levels. Isolating them into pure fractions allows for the reduction of sample complexity, thereby ensuring high quality downstream analysis, such as in protein localization studies. Since the mid-20th century, new methods of subcellular fractionation have constantly emerged. Conventional fractionation approaches based on (ultra)centrifugation typically focus on isolating only one type of organelle. Moreover, their resolving power may be inadequate for improving the limit of detection of downstream applications. Fluorescence-activated organelle sorting (FAOS) is a versatile and advanced technique that is gaining popularity due to its high efficiency. This efficiency refers to the ability to monitor organelle isolation live and to sort multiple organelle populations simultaneously from a single sample. This review offers an overview of the usage of FAOS and highlights its promising prospects within the realm of plant sciences. FAOS shows great potential for applications in both the functional and structural analysis of plant organelles while serving as a valuable isolation tool for downstream applications, including ‘omics’ studies.

@incollection{shankar_microproteins_2026,
	address = {New York, NY},
	title = {Microproteins: {Uncovering} {Hidden} {Layers} of the {Proteome}},
	isbn = {978-1-07-165013-4},
	shorttitle = {Microproteins},
	url = {https://doi.org/10.1007/978-1-0716-5013-4_1},
	abstract = {Once dismissed as nonfunctional transcriptional noise, small open reading frames (sORFs) and their encoded microproteins have rapidly emerged as key players in diverse biological processes. Ranging from just a few to about 150 amino acids in length, microproteins are now recognized for their ability to modulate cellular functions, often acting as dominant-negative regulators, scaffolds, or signaling intermediates. Initially overlooked due to technical and conceptual limitations, they are increasingly being detected thanks to advances in high-resolution proteomics, ribosome profiling, and integrative bioinformatics. In this chapter, we provide a concise overview of the discovery, origins, functions, and biological significance of microproteins. We also introduce the structure of this methods book, which captures the latest experimental and computational tools used to identify, characterize, and functionally dissect microproteins across a wide range of organisms and research disciplines. This emerging field exemplifies the power of cross-disciplinary collaboration, and we hope this volume will support and inspire further research in this exciting and rapidly expanding area.},
	language = {en},
	urldate = {2025-11-21},
	booktitle = {Microproteins: {Methods} and {Protocols}},
	publisher = {Springer US},
	author = {Shankar, Naveen and Wenkel, Stephan},
	editor = {Wenkel, Stephan},
	year = {2026},
	doi = {10.1007/978-1-0716-5013-4_1},
	keywords = {Evolution, Microproteins, Protein structure, lncRNAs, sORFs},
	pages = {3--18},
}

Once dismissed as nonfunctional transcriptional noise, small open reading frames (sORFs) and their encoded microproteins have rapidly emerged as key players in diverse biological processes. Ranging from just a few to about 150 amino acids in length, microproteins are now recognized for their ability to modulate cellular functions, often acting as dominant-negative regulators, scaffolds, or signaling intermediates. Initially overlooked due to technical and conceptual limitations, they are increasingly being detected thanks to advances in high-resolution proteomics, ribosome profiling, and integrative bioinformatics. In this chapter, we provide a concise overview of the discovery, origins, functions, and biological significance of microproteins. We also introduce the structure of this methods book, which captures the latest experimental and computational tools used to identify, characterize, and functionally dissect microproteins across a wide range of organisms and research disciplines. This emerging field exemplifies the power of cross-disciplinary collaboration, and we hope this volume will support and inspire further research in this exciting and rapidly expanding area.

@article{munoz_lysine_2026,
	title = {Lysine potentiates insulin secretion via {AASS}-dependent catabolism and regulation of {GABA} content and signaling},
	volume = {174},
	issn = {0026-0495},
	url = {https://www.sciencedirect.com/science/article/pii/S0026049525002926},
	doi = {10.1016/j.metabol.2025.156423},
	abstract = {Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane depolarization similar to arginine, the role of its intracellular metabolism in β-cell function remains unexplored. Here, we show that lysine acutely potentiates GSIS and that genes encoding enzymes in the lysine degradation pathway, including AminoAdipate-Semialdehyde Synthase (AASS), a key mitochondrial enzyme catalysing the first two steps of lysine catabolism, were present in human pancreatic islets and INS1 832/13 β cells. Some of these genes including AASS, ALDH7A1, DHTKD1, and HADH, were downregulated in pancreatic islets from type 2 diabetes (T2D) versus non-diabetic (ND) donors. Silencing AASS in human islets and INS1 832/13 β cells led to reduced GSIS. Integrated transcriptomics and metabolomics revealed altered expression of GABA metabolism genes, reduced GABA content and accumulation of glutamate in Aass-KD cells. Mitochondrial TCA cycle and OXPHOS function was impaired, evidenced by decreased ATP/ADP ratio, diminished glucose-stimulated mitochondrial respiration, and elevated lactate/pyruvate ratio. Cytosolic calcium responses to glucose and GABA were also disrupted. Pharmacological analyses demonstrated that inhibition of GABA synthesis or degradation did not account for the reduced GSIS, but providing substrates and activation of GDH partially restored insulin secretion, pointing to a diminished glutamate supply as a contributing factor. Remarkably, exogenous GABA restored insulin secretion in β cells and human islets with suppressed AASS-dependent lysine catabolism, supporting a role for GABA as both a metabolic substrate and signaling effector. Together, these findings identify AASS-mediated lysine catabolism as a critical regulator of β-cell metabolic integrity, linking impaired lysine metabolism to GABA depletion, mitochondrial dysfunction, and secretory failure in T2D islets. They also underscore the nutritional importance of essential amino acids such as lysine in sustaining GSIS and glucose homeostasis, and support therapeutic strategies aimed at restoring lysine catabolism or GABA/glutamate balance to maintain β-cell function.},
	urldate = {2025-11-07},
	journal = {Metabolism},
	author = {Muñoz, Felipe and Gao, Qian and Mattanovich, Matthias and Trost, Kajetan and Hodek, Ondřej and Lindqvist, Andreas and Wierup, Nils and Fex, Malin and Moritz, Thomas and Mulder, Hindrik and Cataldo, Luis Rodrigo},
	month = jan,
	year = {2026},
	keywords = {AASS, Amino acids, GABA, GABA shunt, GDH, Glutamate, Insulin secretion, Lysine, Mitochondrial metabolism, TCA cycle, Type 2 diabetes},
	pages = {156423},
}

Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane depolarization similar to arginine, the role of its intracellular metabolism in β-cell function remains unexplored. Here, we show that lysine acutely potentiates GSIS and that genes encoding enzymes in the lysine degradation pathway, including AminoAdipate-Semialdehyde Synthase (AASS), a key mitochondrial enzyme catalysing the first two steps of lysine catabolism, were present in human pancreatic islets and INS1 832/13 β cells. Some of these genes including AASS, ALDH7A1, DHTKD1, and HADH, were downregulated in pancreatic islets from type 2 diabetes (T2D) versus non-diabetic (ND) donors. Silencing AASS in human islets and INS1 832/13 β cells led to reduced GSIS. Integrated transcriptomics and metabolomics revealed altered expression of GABA metabolism genes, reduced GABA content and accumulation of glutamate in Aass-KD cells. Mitochondrial TCA cycle and OXPHOS function was impaired, evidenced by decreased ATP/ADP ratio, diminished glucose-stimulated mitochondrial respiration, and elevated lactate/pyruvate ratio. Cytosolic calcium responses to glucose and GABA were also disrupted. Pharmacological analyses demonstrated that inhibition of GABA synthesis or degradation did not account for the reduced GSIS, but providing substrates and activation of GDH partially restored insulin secretion, pointing to a diminished glutamate supply as a contributing factor. Remarkably, exogenous GABA restored insulin secretion in β cells and human islets with suppressed AASS-dependent lysine catabolism, supporting a role for GABA as both a metabolic substrate and signaling effector. Together, these findings identify AASS-mediated lysine catabolism as a critical regulator of β-cell metabolic integrity, linking impaired lysine metabolism to GABA depletion, mitochondrial dysfunction, and secretory failure in T2D islets. They also underscore the nutritional importance of essential amino acids such as lysine in sustaining GSIS and glucose homeostasis, and support therapeutic strategies aimed at restoring lysine catabolism or GABA/glutamate balance to maintain β-cell function.