SIM2s directed Parkin-mediated mitophagy promotes mammary epithelial cell differentiation

Cell Death Differ. 2023 Jun;30(6):1472-1487. doi: 10.1038/s41418-023-01146-9. Epub 2023 Mar 25.


The functionally differentiated mammary gland adapts to extreme levels of stress from increased demand for energy by activating specific protective mechanisms to support neonatal health. Here, we identify the breast tumor suppressor gene, single-minded 2 s (SIM2s) as a novel regulator of mitophagy, a key component of this stress response. Using tissue-specific mouse models, we found that loss of Sim2 reduced lactation performance, whereas gain (overexpression) of Sim2s enhanced and extended lactation performance and survival of mammary epithelial cells (MECs). Using an in vitro model of MEC differentiation, we observed SIM2s is required for Parkin-mediated mitophagy, which we have previously shown as necessary for functional differentiation. Mechanistically, SIM2s localizes to mitochondria to directly mediate Parkin mitochondrial loading. Together, our data suggest that SIM2s regulates the rapid recycling of mitochondria via mitophagy, enhancing the function and survival of differentiated MECs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors* / genetics
  • Cell Differentiation / genetics
  • Disease Models, Animal
  • Epithelial Cells
  • Female
  • Mice
  • Mitophagy*
  • Ubiquitin-Protein Ligases / genetics


  • Basic Helix-Loop-Helix Transcription Factors
  • Ubiquitin-Protein Ligases