Single-minded-2s: at the nexus of mitophagy and metabolic adaptation during mammary epithelial cell differentiation
Jessica Elswood1, Cole M. McQueen1, Scott J. Pearson1, Emily E. Schmitt1, Steven W. Wall1, H. Ross Payne1, Rola Barhoumi1, Monique Rijnkels1, Weston W. Porter1 1Department of Veterinary Integrative Biosciences; College of Veterinary Medicine; Texas A&M University; College Station, TX 77843, USA
Mitochondria operate as a central hub for many metabolic processes by sensing and responding to the cellular environment to maintain homeostasis. Lactation poses a unique challenge to mitochondrial homeostasis by simultaneously demanding increased production of ATP, milk proteins, and fatty acids, while also mitigating the damage caused by reactive oxygen species. Although morphological differences in mitochondria have been noted between pregnancy and lactation, how these adaptations occur and what implications they have for mammary gland function have not been studied. Using lactogenic differentiation of the HC11 mouse mammary epithelial cell line, we demonstrated that mammary epithelial cells (MECs) attain a highly productive metabolic state during differentiation by engaging both oxidative phosphorylation and glycolysis and that functional differentiation of MECs required an early wave of mitophagy. Moreover, we show that single-minded family bHLH transcription factor 2 short (SIM2s; expressed from Sim2) was localized to mitochondria and enhanced both mitophagy and the energetic capacity of MECs. In cross-fostering experiments, pups nursed by transgenic mice over-expressing Sim2s in the mammary gland gained significantly more weight than those nursed by control dams. Mitochondrial content was reduced in Sim2s over-expressing mammary glands compared to control. Interestingly, mitochondria from Sim2s over-expressing differentiated HC11 cells exhibited enhanced recruitment of the ubiquitin ligase, parkin. Mutation of an ATM phosphorylation site on Sim2 abrogated these effects, and resulted in loss of differentiation status. Furthermore, conditional knockout of Sim2s in the lactating mouse mammary gland resulted in decreased pup weight gain and increased mitochondrial content. Our results suggest a key role for SIM2s and the integration of mitophagy and metabolic adaptation in MEC differentiation, and provide new insight into the complex regulation of mitochondrial homeostasis during mammary gland development.
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