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MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains

Yue Zhang1, Yuchen Xia1, Xinhui Wang1

  • 1Department of Digestive Disease, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Nature Cell Biology
|December 15, 2025
PubMed

Insights

MISO protein organizes specialized mitochondria (SMEM) to maintain mitochondrial DNA (mtDNA) health. Inner mitochondrial stress stabilizes MISO, triggering SMEM assembly and mtDNA degradation.

Area of Science:

  • Cell Biology
  • Mitochondrial Biology
  • Molecular Mechanisms

Background:

  • Mitochondrial dynamics and mtDNA homeostasis are crucial for cellular function.
  • Specialized mitochondrial subdomains, small MTFP1-enriched mitochondria (SMEM), are implicated but poorly understood.
  • The molecular regulators of SMEM formation and their role in mtDNA maintenance are unclear.

Purpose of the Study:

  • To identify and characterize the molecular mechanisms governing SMEM formation.
  • To elucidate the role of MISO in regulating mitochondrial dynamics and mtDNA homeostasis.
  • To understand how inner mitochondrial membrane stresses influence SMEM assembly.

Main Methods:

  • Identified MISO (mitochondrial inner membrane subdomain organizer) as a key regulator.
  • Utilized Drosophila and mammalian cell models.
  • Investigated MISO's role in mitochondrial fusion/fission and SMEM biogenesis using genetic ablation and protein interaction studies.
  • Analyzed the impact of inner mitochondrial membrane stresses on MISO stability and SMEM formation.

Main Results:

  • MISO regulates mitochondrial dynamics by inhibiting fusion (via MTFP1) and promoting fission (via FIS1-DRP1).
  • MISO is essential and sufficient for SMEM biogenesis and facilitates their peripheral fission for mtDNA degradation.
  • Inner mitochondrial membrane stresses (mtDNA damage, OXPHOS dysfunction, cristae disruption) stabilize MISO, initiating SMEM assembly.
  • MISO's C-terminal domain and oligomerization are critical for stress-induced SMEM assembly.

Conclusions:

  • MISO is a conserved protein that orchestrates SMEM formation and mitochondrial dynamics.
  • MISO acts as a crucial link between inner mitochondrial membrane stress and mtDNA homeostasis.
  • This study reveals a novel molecular pathway for regulating mitochondrial quality control via MISO-dependent SMEM organization.

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