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Mitochondrial RNA degradation regulates differentiation, stemness, and immune sensitivity in acute myeloid leukemia

Geethu Emily Thomas1, Veronique Voisin1, Kazem Nouri1,2

  • 1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Nature Communications
|May 30, 2026
PubMed

Insights

Mitochondrial RNA (mtRNA) turnover is elevated in Acute Myeloid Leukemia (AML). Upregulation of SUV3 and PNPase in AML cells degrades mtRNA, and their depletion increases double-stranded RNA (dsRNA), promoting AML differentiation and immune sensitization.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Eukaryotic cells possess distinct nuclear and mitochondrial genomes.
  • Mitochondrial DNA (mtDNA) transcription generates mitochondrial RNA (mtRNA) and double-stranded RNA (dsRNA) as byproducts.
  • Altered RNA metabolism is implicated in various cancers, including Acute Myeloid Leukemia (AML).

Purpose of the Study:

  • To investigate the role of mitochondrial RNA regulation in AML.
  • To identify key factors involved in mtRNA turnover in AML cells and stem cells.
  • To explore the functional consequences of mtRNA dysregulation on AML biology and immune response.

Main Methods:

  • Quantification of mtRNA transcription and degradation rates in AML cells and stem cells.
  • Analysis of mitochondrial degradosome component (SUV3, PNPase) expression in AML.
  • Functional studies involving depletion of SUV3 or PNPase to assess mtRNA and dsRNA levels.
  • Evaluation of IFN-I signaling, AML differentiation, stemness, and immune sensitization following dsRNA accumulation.

Main Results:

  • Increased mtRNA transcription and degradation rates observed in AML cells and stem cells, leading to higher mtRNA turnover.
  • The mitochondrial degradosome components, SUV3 and PNPase, are upregulated in AML cells and stem cells.
  • Depletion of SUV3 or PNPase impairs mtRNA degradation, causing dsRNA accumulation.
  • Accumulated dsRNA stimulates IFN-I signaling, inducing AML differentiation, reducing stemness, and enhancing immune-mediated cytotoxicity.

Conclusions:

  • Mitochondrial RNA regulation plays a significant role in AML pathogenesis.
  • The mitochondrial degradosome (SUV3, PNPase) is crucial for mtRNA and dsRNA degradation in AML.
  • mtRNA turnover influences AML cell differentiation, stem cell properties, and susceptibility to immune attack, offering potential therapeutic targets.

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