bims-smemid 2026-09-20 papers

Nat Metab. 2026 Sep 15.

Cysteine excess triggers a mitochondrial iron-dependent cell death.

Toshitaka Nakamura, Ayaka Inoki, Nupur K Das, Brandon Chen, Artem Khan, Yuyang Liu, Beste Uygur, Frederick S Yen, Gokhan Unlu, Yatrik M Shah, Kıvanç Birsoy.

Thiol-containing metabolites are central to cellular redox homeostasis1. Among these, cysteine functions as a proteogenic amino acid, supports redox balance and iron-sulfur cluster biogenesis, and, when depleted, triggers ferroptosis2. Cells nevertheless maintain cysteine at low levels, reflecting its intrinsic toxicity, but the mechanisms by which excess cysteine causes cell death remain unclear3. Here we performed a genome-wide CRISPR screen and identified mitochondrial iron transporters as essential mediators of cysteine toxicity. Limiting mitochondrial iron availability suppresses cysteine-induced cell death and prevents impairment of iron-sulfur cluster proteins and respiration. Mechanistically, cysteine mobilizes iron from ferritin, expands the cytosolic iron pool and drives mitochondrial iron accumulation. Enhancing glutathione reductase activity specifically within mitochondria restores redox balance downstream of iron accumulation and protects cells by maintaining iron-sulfur cluster integrity. Our findings suggest that maintaining low cysteine levels safeguards mitochondrial iron homeostasis, and that excess cysteine triggers a distinct mitochondrial iron-dependent cell death under conditions of thiol imbalance.

DOI: https://doi.org/10.1038/s42255-026-01616-7

Metabolism. 2026 Sep 18. pii: S0026-0495(26)00291-X. [Epub ahead of print] 156778

SDHB deficiency promotes renal fibrosis by triggering mtRNA leakage and activating the RIG-I-MAVS pathway.

Zijing Zhu, Ping Chen, Hongxin Shu, Qinglin Zeng, Qinghua Luo, Wenping Zhu, Li Yang, TengFeng Yan, Xingen Zhu.

While mutations in tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase B (SDHB) are well-established drivers of renal cell carcinoma via the accumulation of the oncometabolite succinate, its precise role in renal fibrosis remains entirely unexplored. In this study, we demonstrate that SDHB is down-regulated in fibrotic kidneys. Tubule-specific knockdown of Sdhb exacerbated fibrosis, mitochondrial dysfunction, and inflammation in unilateral ureteral obstruction (UUO) mice, while its overexpression exerted protective effects. Mechanistically, SDHB deficiency induced succinate accumulation, which directly bound to residue Leu150 (L150) of voltage-dependent anion channel 1 (VDAC1), promoting VDAC1 oligomerization and triggering mitochondrial RNA (mtRNA) leakage. Cytosolic mtRNA activated the retinoic acid-inducible gene I (RIG-I)-mitochondrial antiviral signaling protein (MAVS) pathway, driving proinflammatory responses. Pharmacological inhibition of VDAC1 oligomerization by VBIT-4 attenuated mtRNA release. Furthermore, we identified E2F transcription factor 4 (E2F4) as an upstream transcriptional activator of SDHB, and overexpression of E2f4 restored SDHB expression and ameliorated renal pathology. These findings provide mechanistic insights into how TCA cycle disruptions and mtRNA leakage interactions drive renal inflammation, suggesting SDHB as a potential therapeutic target for renal fibrosis.

Keywords: Mitochondrial injury; Renal fibrosis; SDHB; mtRNA

DOI: https://doi.org/10.1016/j.metabol.2026.156778

Ecotoxicol Environ Saf. 2026 Sep 16. pii: S0147-6513(26)01142-5. [Epub ahead of print]324 120812

Spatial multi-omics reveals OAT-associated arginine-proline metabolic remodeling in Paraquat-induced Parkinsonian and depression-like phenotypes.

Yu Zhang, Qian Wu, Maming Liu, Nan Lu, Fan Shen, Jingyi Cai, Qian Yang, Shou Lin, Min Zhang, Chenjing Ye.

Paraquat (PQ) is a highly toxic bipyridyl herbicide that remains in agricultural use in some regions despite bans or severe restrictions elsewhere and is also widely used as a model toxicant for investigating environmentally induced neurodegeneration. However, the spatial metabolic alterations associated with PQ-induced neurobehavioral impairment remain incompletely understood. In this study, we performed AFADESI-MSI-based spatial metabolomic profiling and Visium spatial transcriptomic profiling on PQ-exposed mouse brains, and integrated these analyses with targeted metabolite assays, molecular validation and pharmacological intervention. PQ exposure induced motor coordination deficits, anhedonia-like behavior, increased behavioral despair and systemic metabolic disruption, including altered glucose, lipid and lactate metabolism. Spatial metabolomics showed that PQ did not cause a uniform whole-brain metabolic shift, but instead induced redistribution of multiple metabolic components across anatomically distinct brain regions. Region-resolved metabolomic analysis of the amygdala, cortex, hippocampus, thalamus and hypothalamus identified recurrent differential metabolites and PQ-associated co-abundance modules prominently enriched in arginine and proline metabolism. Within this pathway, L-arginine, citrulline, L-proline and glutamate were increased across multiple regions, whereas L-ornithine remained largely unchanged. ST profiling suggested increased Oat expression signals, while immunofluorescence and enzyme activity assays further confirmed increased ornithine aminotransferase (OAT) protein expression and activity. Virtual Oat perturbation implicated neurotransmission, synaptic plasticity and neurodegeneration-related pathways, while pharmacological OAT inhibition with 5-fluoromethylornithine reduced PQ-enhanced OAT activity and partially improved behavioral abnormalities. These findings support OAT-associated arginine and proline metabolic remodeling as a spatially distributed metabolic feature of PQ-induced Parkinsonian motor deficits and depression-like phenotypes, providing a brain-region-resolved metabolic perspective on environmental neurotoxicity.

Keywords: Arginine and proline metabolism; Depression; OAT; Paraquat; Parkinson’s disease; Spatial metabolomics; Spatial transcriptomics

DOI: https://doi.org/10.1016/j.ecoenv.2026.120812

Sci Rep. 2026 09 16. pii: 28863. [Epub ahead of print]16(1):

Cyclosporin A triggers a RIG-I-mediated interferon response through multiple cellular processes.

Lars Meier, Martin Schauflinger, Pauline Neubecker, Dennis Freisem, Lena Gimpl, Michelle Gellhorn Serra, Helene Hoenigsperger, Benjamin Rupf, Susanne Herold, Stefan Bauer, Konstantin M J Sparrer, Stephan Becker, Lucie Sauerhering.

The development of broad-spectrum antiviral agents is essential for preparedness against emerging viruses with pandemic potential. Cyclosporin A (CsA), a clinically approved immunosuppressant, has been shown to exert antiviral activity against a wide range of viruses. Recent evidence suggests that this effect is partially mediated through the induction of interferon lambda (IFN-λ), which in turn stimulates a set of interferon-stimulated genes (ISGs) that establish an antiviral cellular state. However, the molecular mechanisms underlying IFN-λ induction by CsA have remained poorly understood. Here, we demonstrate that CsA triggers a retinoic acid-inducible gene I (RIG-I)-dependent activation of the IFN-λ/ISG signaling axis. This is accompanied by the upregulation of mitochondrial double-stranded RNA (dsRNA). Importantly, we show that CsA causes pronounced alterations in the mitochondrial cristae network. CsA also impairs autophagy, as evidenced by reduced autophagosomal membrane formation and increased levels of the autophagy marker p62. Supporting a functional link, treatment with the autophagy inducer Torin-1 reverses CsA-induced dsRNA accumulation, IFN-λ expression and ISG transcription. Together, our data indicate that the antiviral activity of CsA is partially driven by converging cellular processes involving mitochondrial remodeling, dsRNA accumulation, and impaired autophagy, which collectively activate the RIG-I/IFN-λ/ISG axis, offering mechanistic insights with therapeutic implications.

Keywords: Cyclosporin A (CsA); Drug repurposing; Mitochondria; Type III interferon

DOI: https://doi.org/10.1038/s41598-026-68563-x