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Author Spotlight: Advancing Techniques and Discoveries in Protein Synthesis and Assembly Through Innovative Mitochondrial Research
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Author Spotlight: Advancing Techniques and Discoveries in Protein Synthesis and Assembly Through Innovative Mitochondrial Research

Published on: June 7, 2024

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Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML

Guoqiang Han1, Manman Cui1, Pengbo Lu1

  • 1Department of Hematology, Zhongnan Hospital, Medical Research Institute, Wuhan University, Wuhan, China; State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China.

Cell Stem Cell
|October 2, 2024
PubMed

Insights

Researchers identified RREB1 as a key regulator of mitochondrial protein translation in acute myeloid leukemia (AML). This finding uncovers a new vulnerability in leukemia stem cells (LSCs) and suggests novel therapeutic strategies for AML.

Area of Science:

  • Cancer Biology
  • Molecular Biology
  • Metabolism

Background:

  • Mitochondrial adaptations are crucial for cancer cell bioenergetics and metabolism.
  • The precise regulation of mitochondrial responses in cancer remains poorly understood.
  • Acute myeloid leukemia (AML) relies on specific mitochondrial functions.

Purpose of the Study:

  • To identify regulators of mitochondrial responses in human cancers, specifically AML.
  • To uncover a novel translation control system for nuclear-encoded mitochondrial proteins.
  • To explore RREB1 as a potential therapeutic target in AML.

Main Methods:

  • Genetic screening in AML models.
  • Identification and characterization of RREB1 as a translational regulator.
  • Analysis of mitochondrial activity, succinate metabolism, and leukemia stem cell (LSC) function.
  • Investigating the role of RREB1 variants and elongation factor eEF1A1.
  • Assessing the impact of complex II inhibition on venetoclax sensitivity.

Main Results:

  • RREB1 was identified as a translational regulator of nuclear-encoded mitochondrial proteins in cancer.
  • RREB1 deletion impaired mitochondrial activity, succinate metabolism, and LSC function in AML.
  • Restoring complex II subunit SDHD corrected these deficiencies.
  • Inhibition of complex II re-sensitized AML cells to venetoclax.
  • A short RREB1 variant binds to 3' UTRs and enhances mitochondrial mRNA translation via eEF1A1.

Conclusions:

  • A unique translation control mechanism for mitochondrial adaptations in AML pathogenesis has been revealed.
  • RREB1 plays a critical role in regulating mitochondrial function and LSC viability.
  • Targeting this RREB1-mediated translation control offers a potential strategy against AML LSCs.
Keywords:
RREB1SDHDacute myeloid leukemialeukemia stem cellmitochondriasuccinatetranslationvenetoclax

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