Vascular endothelial injury initiates atherosclerosis (AS) progression. N -Acetylneuraminic acid (Neu5Ac) metabolic disorder was found to intensify endothelial mitochondrial damage. And GLS2-associated glutaminolysis disorder contributed to mitochondrial dysfunction. However, mechanisms underlying Neu5Ac-associated mitochondrial dysfunction as well as its association with GLS2 remains unclear. In this study, we constructed GLS2 −/− ApoE −/− mice by using HBLV-GLS2 shRNA injection. And methods like immunofluorescence, western blotting, transmission electron microscopy were applied to detect profiles of endothelial injury and AS progression both in vivo and in vitro. We demonstrated that Neu5Ac accumulation increased GLS2 expression and promoted glutaminolysis disorder, which further induced endothelial mitochondrial dysfunction via a pyroptosis-dependent pathway in vivo and in vitro. Mechanically, Neu5Ac interacted with SIRT3 and led to FOXO3a deacetylation and phosphorylation, further facilitated c-Myc antagonism and ultimately increased GLS2 levels. Inhibition of GLS2 could improve mitochondrial function and mitigate pyroptosis process. In addition, blocking Neu5Ac production using neuraminidases (NEUs) inhibitor could rescue endothelial damage and alleviate AS development in ApoE −/− mice. These findings proposed that Neu5Ac induced GLS2-mediated glutaminolysis disorder and then promoted mitochondrial dysfunction in a pyroptosis-dependent pathway. Targeting GLS2 or inhibiting Neu5Ac production could prevent AS progression.
Bo Pang,Siyuan Chen,Yikai Bai,Yan Zhang,Zhida Wang
Diabetic peripheral neuropathy (DPN) is a prevalent complication characterized by Schwann cell dysfunction. The role of the nuclear receptor subfamily 4 group member 3 (NR4A3) in DPN remains unclear. We found that NR4A3 expression is upregulated in the sciatic nerves of streptozotocin (STZ)-induced DPN mice. Overexpression of NR4A3 via AAV9-Mpz-NR4A3 lumbar intrathecal injection improved motor and sensory nerve function and mitigated sciatic nerve pathology. NR4A3 overexpression also reduced oxidative stress and enhanced mitochondrial function. In the high glucose (HG)-induced Schwann cell injury model, NR4A3 overexpression inhibited apoptosis, mitochondrial dysfunction, and dedifferentiation. Integrated ChIP-seq and mRNA-seq profiling identified glutaminase 2 (GLS2) as a direct transcriptional target of NR4A3. NR4A3 bound to the GLS2 promoter and promotes its transcriptional activation, and suppression of GLS2 abrogated the functional protection conferred by NR4A3 in Schwann cells. Together, NR4A3 represents a promising therapeutic target for DPN.
Lu Han,Die Zhang,Weidong Xiao,Chunyan Zeng,Youxiang Chen
Background Pancreatic ductal adenocarcinoma (PDAC) undergoes profound metabolic reprogramming. This study aims to elucidate how PIK3CG deficiency drives glutamine (Gln) metabolic reprogramming in PDAC. Methods We first identified PIK3CG as a key differentially expressed gene in PDAC and confirmed that its expression level correlates with patient survival. We established both in vitro and in vivo PIK3CG -knockdown ( PIK3CG -KD) models. Using these models, we assessed its regulatory effects on the Gln metabolic pathway, mitochondrial reactive oxygen species (mtROS) accumulation, mitochondrial membrane potential, and tumor cell pyroptosis. Moreover, we delineated the specific molecular mechanism linking PIK3CG to downstream signaling. This mechanism crucially involves GLS2 , a key enzyme in glutamine metabolism. Results PIK3CG deficiency suppresses the mechanistic target of rapamycin complex 1 (mTORC1) pathway, leading to enhanced phosphorylation of S6K2. This disrupts the interaction between nuclear S6K2 (Glu163) and P53 (Arg273), ultimately inhibiting GLS2 transcription. Consequently, a series of metabolic disturbances ensue: glutamate (Glu) accumulates substantially, Gln catabolism is blocked, and its influx into the TCA cycle is restricted, resulting in reduced α-ketoglutarate (α-KG) levels. The deficiency in α-KG triggers a significant accumulation of mtROS. Notably, despite elevated ROS levels, pyroptosis is suppressed and accompanied by exacerbated inflammation. Conversely, GLS2 overexpression rescues all the aforementioned phenotypes induced by PIK3CG -KD—including tumor growth, elevated mtROS, suppression of pyroptosis, and inflammatory response—while restoring Gln metabolic homeostasis. Conclusion Our study reveals a novel mechanism by which PIK3CG -KD regulates Gln metabolism and mitochondrial function via the S6K2/P53/GLS2 axis, providing a rationale for metabolic intervention and precision therapy in PIK3CG -deficient PDAC.
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