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Mitochondrial dynamics as a potential therapeutic target in acute myeloid leukemia

Mariko Kinoshita1, Yusuke Saito2, Kento Otani3

  • 1Division of Pediatrics, Faculty of Medicine, University of Miyazaki, 5200, Kihara, Kiyotake, Miyazaki, 889-1692, Japan. mariko_kinoshita@med.miyazaki-u.ac.jp.

International Journal of Hematology
|September 16, 2024
PubMed

Insights

Targeting mitochondrial dynamics, essential for acute myeloid leukemia (AML) cell growth, offers a promising therapeutic strategy. Inhibiting fission-related genes like MFF and DNM1L significantly impaired AML cell proliferation and improved survival in mice.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Acute myeloid leukemia (AML) cells rely heavily on oxidative phosphorylation.
  • Mitochondrial dynamics, regulated by fusion (MFN1, MFN2, OPA1) and fission (DNM1L, MFF) genes, are critical for AML cell function.
  • High MFF expression correlates with poor prognosis in AML patients.

Purpose of the Study:

  • To investigate the role of mitochondrial dynamics in AML.
  • To explore the therapeutic potential of targeting mitochondrial fission in AML.

Main Methods:

  • Gene expression analysis of published datasets.
  • shRNA-mediated knockdown of DNM1L and MFF in AML cell lines.
  • Extracellular flux analysis to assess cellular respiration and glycolysis.
  • In vivo studies using immunodeficient NOG mice.
  • Pharmacological inhibition of DNM1L using Mdivi-1.

Main Results:

  • Knockdown of DNM1L or MFF inhibited AML cell growth and increased mitochondrial area.
  • Mitochondrial dynamic regulator deletion reduced oxidative phosphorylation without significantly impacting glycolysis (except in shDNM1L cells).
  • DNM1L or MFF knockdown in AML cells led to significantly longer survival in NOG mice.
  • Mdivi-1 treatment inhibited AML cell proliferation and oxidative phosphorylation.

Conclusions:

  • Mitochondrial dynamics are crucial for AML pathogenesis.
  • Inhibition of mitochondrial dynamics induces unique mitochondrial alterations in AML.
  • Targeting mitochondrial dynamics presents a novel therapeutic strategy for AML.
Keywords:
AMLDNM1LMFFMdivi-1Mitochondrial dynamics

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