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Updated: Apr 7, 2026

Visualization of Endogenous Mitophagy Complexes In Situ in Human Pancreatic Beta Cells Utilizing Proximity Ligation Assay
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Phase separation of C19orf12 regulates BNIP3 protein quality control and maintains neuronal mitophagy

Changjuan Shao1, Sabina Bhatta1, Meena Kumari1

  • 1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Autophagy
|April 6, 2026
PubMed

Insights

Mutations in C19orf12 cause mitochondrial membrane protein-associated neurodegeneration (MPAN). This study reveals C19orf12 is crucial for mitophagy by regulating BNIP3 turnover, and its dysfunction leads to MPAN pathology.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Mutations in C19orf12 cause mitochondrial membrane protein-associated neurodegeneration (MPAN), a disorder with unclear pathogenic mechanisms.
  • Mitochondrial deficits are observed in MPAN, but the precise role of C19orf12 in these deficits remains elusive.

Purpose of the Study:

  • To investigate the functional impact of C19orf12 mutations on mitophagy.
  • To elucidate the role of C19orf12 in the pathogenesis of MPAN.

Main Methods:

  • In vitro and in vivo MPAN models were utilized.
  • Investigated the regulation of mitophagy receptor BNIP3 protein turnover.
  • Analyzed protein condensate formation via liquid-liquid phase separation.

Main Results:

  • C19orf12 regulates BNIP3 protein turnover via lysosomal degradation.
  • Disruption of C19orf12 function leads to ineffective mitophagy due to oxidized BNIP3 accumulation on mitochondria.
  • C19orf12 facilitates BNIP3 turnover through liquid-liquid phase separation in protein condensates.
  • MPAN rodent models exhibit motor deficits, iron accumulation, axonal spheroids, and neuroinflammation.

Conclusions:

  • C19orf12 plays a critical role in maintaining mitochondrial quality control by regulating BNIP3 protein turnover and mitophagy.
  • Impaired mitophagy due to C19orf12 dysfunction is a significant factor in MPAN pathogenesis.
  • Understanding C19orf12's role in mitophagy offers potential therapeutic targets for MPAN.
Keywords:
Iron accumulationLLPSNBIAmitochondrial membranemitophagosomeprotein degradation

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