Authors
Zijing Zhu, Ping Chen, Hongxin Shu, Qinglin Zeng, Qinghua Luo, Wenping Zhu, Li Yang, TengFeng Yan, Xingen Zhu
Published in
Metabolism: clinical and experimental. Pages 156778. Sep 18, 2026. Epub Sep 18, 2026.
Abstract
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.
PMID:
42759926
Bibliographic data and abstract were imported from PubMed on 19 Sep 2026.
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