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Updated: Aug 9, 2026

Simultaneous Measurement of Superoxide/Hydrogen Peroxide and NADH Production by Flavin-containing Mitochondrial Dehydrogenases
08:57

Simultaneous Measurement of Superoxide/Hydrogen Peroxide and NADH Production by Flavin-containing Mitochondrial Dehydrogenases

Published on: February 24, 2018

The mitochondria enzyme OGDH defends against disulfidptosis by licensing METTL3-regulated NRF2 translation

Xiao-Yan Chen1, Ke-Jun Xu1, Jia-Xin Zhou1

  • 1State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Xiamen University, Xiamen, China.

Nature Cell Biology
|August 7, 2026
PubMed

Insights

Melanoma cells evade disulfidptosis, a cell death pathway, by using the HSPA9-OGDH-METTL3-NRF2 axis. Targeting this axis and glucose uptake may inhibit melanoma growth.

Area of Science:

  • Oncology
  • Cell Death Mechanisms
  • Metabolic Regulation

Background:

  • Disulfidptosis is regulated cell death induced by disulfide stress from glucose starvation.
  • Tumor cells require mechanisms to evade disulfidptosis for survival in glucose-limited environments.

Purpose of the Study:

  • To identify key regulators of disulfidptosis evasion in melanoma.
  • To elucidate the molecular mechanisms underlying melanoma cell resistance to disulfidptosis.
  • To explore potential therapeutic strategies targeting disulfidptosis evasion in melanoma.

Main Methods:

  • Investigated the role of OGDH (oxoglutarate dehydrogenase) in disulfidptosis resistance.
  • Examined the protective function of HSPA9 (Heat Shock Protein Family A Member 9) on OGDH activity under glucose deprivation.
  • Analyzed the downstream signaling pathway involving METTL3 (methyltransferase-like 3) succinylation, NRF2 (Nuclear factor erythroid 2-related factor 2) translation, and TrxR1 (Thioredoxin Reductase 1) expression.
  • Evaluated the efficacy of combined HSPA9 suppression and glucose uptake inhibition in melanoma mouse models.
  • Correlated HSPA9 and OGDH expression with disulfidptosis signature and clinical prognosis in melanoma patients.

Main Results:

  • OGDH is critical for conferring resistance to disulfidptosis.
  • HSPA9 protects OGDH from oxidative inactivation during glucose starvation, facilitating succinyl-CoA production for METTL3 succinylation.
  • Succinylated METTL3 promotes NRF2 translation and TrxR1 expression, leading to disulfidptosis evasion.
  • Combined suppression of HSPA9 and glucose uptake significantly inhibits melanoma growth in vivo.
  • High HSPA9 and OGDH expression in melanoma patients correlates with a poor prognosis and reduced disulfidptosis signature.

Conclusions:

  • Melanoma cells depend on the HSPA9-OGDH-METTL3-NRF2 signaling axis to evade disulfidptosis.
  • This axis represents a potential therapeutic target for melanoma treatment.
  • Combined inhibition of HSPA9 and glucose uptake offers a promising therapeutic strategy for melanoma.

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