39 Oral - Physiology, Aging, and Metabolism I
Thursday April 07, 6:15 PM - 6:30 PM

Authors:
Zong-Heng Wang ¹; Christian Combs ¹; Jay Knutson ¹; Yongshun Lin ¹; Jizhong Zou ¹; Mary Lilly ²; Hong Xu ¹

Affiliations:
1) National Heart, Lung, and Blood Institute, Bethesda, MD; 2) National Institute of Child Health and Human Development, Bethesda, MD

Keywords:
h. mitochondria; j. other signaling pathways

Mitochondria affords eukaryotes great metabolic flexibility to balance energy metabolism and cellular homeostasis. Unicellular organisms can adjust metabolic programs response to the availability of nutrients in environment. In multicellular organisms, a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) is often observed during the differentiation of various types of stem cells and progenitors. To support proliferation, cells emphasize on glycolysis to preserve carbon sources for biosynthetic pathways. Post-mitotic cells utilize OXPHOS, a more effective way producing ATP, to power cellular activities. However, the cellular processes orchestrate this metabolic transition are largely unknown. We previously demonstrated that mitochondrial biogenesis and OXPHOS are activated in the differentiating ovarian cyst in Drosophila. Here, we report that mechanical forces generated by the surrounding somatic cells trigger JNK signaling and mitochondrial energy metabolism in differentiating germ cells. Somatic cells compress the differentiating cyst. Using fluorescence lifetime imaging microscopy (FLIM), we found that compression increases the membrane tension of germ cells. Abolishing somatic cells’ engulfment by genetically inhibiting Notch signaling, relieves the membrane tension on germ cells and blocks the activation of OXPHO activity as well. We carried out candidate RNAi screen on genes involved in mechanosensation and identified that the stretch-activated ion channel (SAC), Tmc, is required for OXPHOS activation. In compressed differentiating cysts, gating of Tmc maintains cytosolic Ca²⁺ levels, which induces the transcriptional activation of OXPHOS through a CaMKI-Fray-JNK signaling relay. Moreover, our preliminary data show that SACs mediate contraction-induced OXPHOS during the maturation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), suggesting that mechanical activation of mitochondrial energy metabolism is evolutionarily conserved among animals.