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Elevated SFXN2 limits mitochondrial autophagy and increases iron-mediated energy production to promote multiple

Ying Chen1,2, Jinjun Qian2, Pinggang Ding2

  • 1Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, China.

Cell Death & Disease
|September 26, 2022
PubMed

Insights

Human sideroflexin 2 (SFXN2) is elevated in multiple myeloma (MM) and promotes cancer cell growth by disrupting mitochondrial iron metabolism and autophagy. Inhibiting SFXN2 shows therapeutic potential for MM treatment.

Area of Science:

  • Mitochondrial biology
  • Cancer metabolism
  • Hematology

Background:

  • Mitochondrial outer membrane protein sideroflexin 2 (SFXN2) plays a role in mitochondrial iron metabolism.
  • The precise function of SFXN2 in multiple myeloma (MM) and its impact on mitochondrial homeostasis remain unclear.

Purpose of the Study:

  • To investigate the role of SFXN2 in the pathogenesis of multiple myeloma.
  • To explore the potential of SFXN2 as a therapeutic target in MM.

Main Methods:

  • Analysis of clinical datasets to correlate SFXN2 levels with MM patient outcomes.
  • In vitro studies using MM cell lines (ARP1, H929) to assess the effects of SFXN2 overexpression and knockdown on cell proliferation, autophagy, and mitophagy.
  • In vivo studies using a myeloma xenograft model to evaluate the anti-myeloma activity of SFXN2 inhibition.
  • Mechanistic studies to elucidate the involvement of heme oxygenase 1 (HO1) in SFXN2-mediated processes.

Main Results:

  • SFXN2 expression is significantly elevated in MM patients and correlates with poor prognosis.
  • SFXN2 overexpression enhances MM cell proliferation and suppresses starvation-induced autophagy/mitophagy.
  • SFXN2 knockdown exacerbates mitochondrial damage and enhances autophagic processes in MM cells.
  • Inhibition of SFXN2 demonstrates significant anti-myeloma activity in vivo.
  • Heme oxygenase 1 (HO1) contributes to SFXN2-mediated autophagy suppression and proliferation.

Conclusions:

  • SFXN2 is a critical regulator of mitochondrial bioenergetics, mitophagy, iron metabolism, and redox homeostasis in MM.
  • SFXN2 plays a significant role in MM cell proliferation and survival.
  • Targeting SFXN2, potentially in conjunction with iron metabolism modulation, offers a promising therapeutic strategy for MM.

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