Jul 2026· Biochemical and Biophysical Research Communications - BBRC· Vol 830, pp.
154293
· 0 citations· 23 references
Medicine
TL;DR
Findings suggest that UFC1 contributes to ACSL3 protein abundance, probably through UFMylation-associated suppression of proteasomal degradation, thereby supporting lipid homeostasis and proliferation in skeletal muscle myoblasts.
Abstract
Ordered proliferation of skeletal muscle myoblasts is essential for muscle development and repair and requires coordinated metabolic remodeling. Acyl-CoA synthetase long-chain family member 3 (ACSL3) activates long-chain fatty acids and thereby supports lipid metabolic flux, but the post-translational mechanisms regulating ACSL3 in myoblasts remain incompletely defined. UFMylation is a ubiquitin-like post-translational modification mediated by a cascade that includes the E2-conjugating enzyme UFC1. Here, we investigated whether UFC1 regulates ACSL3 abundance and lipid metabolism in C2C12 myoblasts and primary mouse skeletal muscle myoblasts. UFC1 knockout or knockdown reduced ACSL3 protein abundance, decreased myoblast proliferation, and lowered cellular neutral and polar lipid signals. Transcriptomic gene set enrichment analysis further indicated suppression of pathways related to unsaturated fatty acid biosynthesis and fatty acid metabolism after UFC1 loss. Co-immunoprecipitation showed an association between UFC1 and ACSL3, and endogenous immunoprecipitation detected a UFC1-dependent UFM1 signal on ACSL3. Cycloheximide chase assays indicated accelerated ACSL3 degradation in UFC1-deficient cells, whereas the proteasome inhibitor MG132 partially restored ACSL3 protein abundance. Overexpression of ACSL3 alleviated lipid metabolic defects and partially rescued proliferation in UFC1-deficient myoblasts. These findings suggest that UFC1 contributes to ACSL3 protein abundance, probably through UFMylation-associated suppression of proteasomal degradation, thereby supporting lipid homeostasis and proliferation in skeletal muscle myoblasts.
Upon antigen stimulation, naïve CD4⁺ T cells undergo rapid metabolic remodeling that supports immune responses. Lipid metabolism has emerged as a critical regulator of T-cell proliferation, effector function, and memory formation, and has been proposed as a potential therapeutic target in immune-related diseases. However, how T cells adapt to perturbation in lipid metabolism remains unclear. To address this question, we performed integrative multi-omics analyses in EL4 T cells, including transcriptomics, proteomics, phosphoproteomics, and lipidomics, to investigate metabolic adaptation under conditions of impaired fatty acid biosynthesis. In EL4 T cells, disruption of acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme of fatty acid biosynthesis, reduced lipid droplet abundance and enhanced fatty acid uptake. Transcriptomic and proteomic analyses revealed upregulation of fatty acid transporters such as CD36 and SLC27A4, and functional disruption of these transporters attenuated the increased fatty acid uptake. Lipidomic analysis further showed widespread reductions in neutral lipid species and increased phospholipid unsaturation. Moreover, phosphoproteomic analysis implicated the mTOR signaling pathway, and pharmacological inhibition of mTOR suppressed the elevated fatty acid uptake in ACC1-deficient cells. Collectively, these findings reveal unrecognized mechanisms of lipid metabolic adaptation and highlight a regulatory network that coordinates fatty acid uptake in response to impaired lipid synthesis.
Takeru Endo, T. Kanno, R. Konno et al.· Scientific Reports· 0 citations
Autophagy maintains cellular homeostasis by degrading and recycling intracellular components, while the selective clearance of damaged mitochondria, known as mitophagy, ensures mitochondrial quality control. Protein complexes orchestrate these processes, yet their dynamic regulation remains incompletely understood. Here, we integrate thermal proteome profiling with co-aggregation analysis to monitor protein thermal stability and complex assembly dynamics in response to two canonical inducers: Torin 1, which activates autophagy via mTOR inhibition, and CCCP, a mitochondrial uncoupler that triggers mitophagy. This endeavor provides a global view of the dynamic variations of known autophagy- and mitophagy-associated complexes, revealing their assembly state at various stages. Notably, we identify previously uncharacterized complexes containing the eukaryotic elongation factor 1 A1 (EEF1A1) that exhibit enhanced aggregation under both treatments. Functional analyses show that EEF1A1 depletion impairs autophagosome maturation and mitophagic degradation, while pulsed-SILAC demonstrates that EEF1A1 directly regulates the synthesis of core autophagy proteins. Together, these findings map the dynamic landscape of protein complex regulation during autophagy and mitophagy and uncover EEF1A1-mediated translational control as a previously unrecognized regulatory mechanism.
Shuang Zhang, Ya Zeng, Fengming Li et al.· Cell Communication and Signa...· 0 citations
Emerging evidence has shown that fatty acid metabolism is closely associated with autoreactive T cells in autoimmunity, but its function in Sjögren's syndrome (SS) is still unclear. Here, we identified acyl-CoA synthetase long-chain family member 5 (ACSL5) as a metabolic checkpoint that drives pathogenic T-cell responses in SS. ACSL5 was upregulated in patients with SS and positively correlated with T-cell infiltration and lipid dysregulation. ACSL5-high T cells presented hyperactive effector activity and a proinflammatory phenotype. Metabolic profiling indicated that ACSL5 increased fatty acid uptake and utilization and promoted fatty acid oxidation (FAO) through peroxisome proliferator-activated receptor alpha (PPARα) in T cells, thereby improving mitochondrial respiratory capacity. Mechanistically, ACSL5 facilitated the nuclear translocation of PPARα and subsequent Mitofusin 2 (MFN2) transcription, increasing mitochondrial elongation and the formation of mitochondria‒endoplasmic reticulum contacts (MERCs) to influence the FAO and T-cell response. Disruption of the ACSL5/PPARα/MFN2 axis attenuated effector functions and reduced the longevity of pathogenic effector T cells. Pharmacological inhibition of FAO or ACSL5 decreased inflammatory T-cell infiltration and alleviated salivary gland inflammation. Collectively, these findings reveal an ACSL5-centered metabolic program that sustains pathogenic T-cell responses in SS and suggest ACSL5/FAO as a potential therapeutic target.
Xinyi Ren, Junhao Yin, Xinyi Ma et al.· International Journal on Bio...· 0 citations
TMEM135 has been implicated in lipid metabolism, but its role in regulating hepatic lipid homeostasis remains unclear. Here, we investigated how TMEM135 affects hepatic lipid metabolism using Tmem135 mutant mice with liver-specific Pex5 deletion. The Tmem135 mutation induced a lipogenic state characterized by depletion of docosahexaenoic acid (DHA), activation of SREBP-dependent pathways, and increased monounsaturated fatty acids without causing hepatic steatosis. In contrast, loss of PEX5-dependent peroxisomal function in Tmem135 mutant mice resulted in marked hepatic lipid accumulation, indicating that peroxisomal metabolism buffers the elevated lipogenic state. Fish oil supplementation to Tmem135 mutant mice restored DHA levels and suppressed lipogenesis. Proteomics identified distinct DHA-sensitive metabolic programs, including activation of SREBP-dependent lipogenesis. Quantitative malonyl-proteomics revealed increased malonylation of glycolytic enzymes, accompanied by altered glycolytic output. Together, these findings identify TMEM135 as a central regulator of hepatic lipid metabolism and uncover a coordinated mechanism linking lipid availability, lipogenesis, and post-translational metabolic regulation. Highlight Tmem135 mutation induces a lipogenic state with increased lipolysis without hepatic steatosis. PEX5-dependent peroxisomal function buffers lipid accumulation in Tmem135 mutant liver. Fish oil supplementation restores DHA and suppresses SREBP-dependent lipogenesis in Tmem135 mutants. DHA-sensitive protein malonylation targets glycolytic enzymes in Tmem135 mutant liver.
Ryo Hagimori, Michael Landowski, Siyu Song et al.· bioRxiv· 0 citations
ABSTRACT SLC25A46 is a mitochondrial intermembrane bridging protein reported to play a crucial role in mitochondrial network maintenance, yet its functional roles in human cancer metabolic rewiring and disease progression remain unexplored, including ovarian cancer (OC). Here, we revealed that SLC25A46 is markedly upregulated in OC and associated with poor patient outcomes. Functionally, SLC25A46 promoted OC growth by facilitating cell proliferation and ferroptosis evasion. Mechanistically, SLC25A46 promotes cell proliferation and ferroptosis evasion of OC cells by activating fatty acid oxidation‐mediated ATP and NADPH production via protecting carnitine‐acylcarnitine translocase (CACT) from MARCHF5‐mediated ubiquitin‐degradation. Notably, knockdown of SLC25A46 significantly increased the sensitivity of OC cells to ferroptosis and enhanced their cytotoxic response to carboplatin. Additionally, we found that PBX1 directly binds and transactivates the SLC25A46 promoter. Overall, our results highlight the critical role of SLC25A46/MARCHF5/CACT axis in facilitating cell proliferation and ferroptosis evasion in OC cells via activating fatty acid oxidation‐mediated ATP and NADPH production. These findings suggest that targeting SLC25A46 represents a rational strategy to improve treatment outcomes in OC patients.
Yunge Gao, Jiatao Hao, Xiaohong Zhang et al.· Advancement of science· 0 citations
Restoring lipid droplet (LD) content has been reported to reverse hepatic stellate cell (HSC) activation during liver fibrosis. Although the mitochondrial citrate carrier SLC25A1 is known to drive metabolic reprogramming in cancer and steatohepatitis, its specific role in regulating LDs remains unclear. This study aimed to elucidate the role of SLC25A1 in controlling LD homeostasis during HSC activation and to determine whether therapeutic inhibition of SLC25A1 could ameliorate liver fibrosis by restoring peroxisome proliferator-activated receptor-γ (PPARγ)-dependent lipid storage. Knockdown of Slc25a1 was achieved using either an adeno‑associated viral vector expressing Slc25a1 short hairpin RNA or hyaluronic acid-modified, HSC membrane-biomimetic nanovesicles containing Slc25a1 small interfering RNA (HA@JMNVs/siSlc25a1). Both approaches effectively attenuated HSC activation in three distinct mouse models, induced by carbon tetrachloride, methionine- and choline-deficient diet, and bile duct ligation, respectively. Mechanistically, SLC25A1 deficiency reduced cytosolic acetyl-coenzyme A levels in activated the human immortalized hepatic stellate cell line LX-2, resulting in reduced overall acetylation of neural precursor cell expressed, developmentally downregulated 4 (NEDD4). This reduction subsequently suppressed the NEDD4-mediated ubiquitination and degradation of PPARγ at lysine 197 (K197). The metabolic-post-translational signaling cascade increased perilipin-2 (PLIN2) transcription, inhibited lipophagy, and ultimately restored LD accumulation, thereby reversing HSC activation. Collectively, these findings establish the SLC25A1-regulated metabolic axis as a promising therapeutic target and offer a robust preclinical proof-of-concept for targeted gene therapies against liver fibrosis.
Shuqin Xue, Xiujuan Yin, Sicheng Shu et al.· Pharmacological Research· 0 citations
