RESUMO
Physical contact between organelles is vital to the function of eukaryotic cells. Lipid droplets (LDs) are dynamic organelles specialized in lipid storage that interact physically with mitochondria in several cell types. The mechanisms coupling these organelles are, however, poorly understood, and the cell-biological function of their interaction remains largely unknown. Here, we discover in adipocytes that the outer mitochondrial membrane protein MIGA2 links mitochondria to LDs. We identify an amphipathic LD-targeting motif and reveal that MIGA2 binds to the membrane proteins VAP-A or VAP-B in the endoplasmic reticulum (ER). We find that in adipocytes MIGA2 is involved in promoting triglyceride (TAG) synthesis from non-lipid precursors. Our data indicate that MIGA2 links reactions of de novo lipogenesis in mitochondria to TAG production in the ER, thereby facilitating efficient lipid storage in LDs. Based on its presence in many tissues, MIGA2 is likely critical for lipid and energy homeostasis in a wide spectrum of cell types.
Assuntos
Adipócitos/metabolismo , Lipogênese/fisiologia , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Células 3T3 , Adipócitos/fisiologia , Animais , Células COS , Diferenciação Celular/fisiologia , Chlorocebus aethiops , Retículo Endoplasmático/metabolismo , Células HEK293 , Humanos , Gotículas Lipídicas/metabolismo , Lipogênese/genética , Proteínas de Membrana/fisiologia , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/fisiologia , Triglicerídeos/biossíntese , Proteínas de Transporte Vesicular/metabolismoRESUMO
Similar to tumor-initiating cells (TICs), minimal residual disease (MRD) is capable of reinitiating tumors and causing recurrence. However, the molecular characteristics of solid tumor MRD cells and drivers of their survival have remained elusive. Here we performed dense multiregion transcriptomics analysis of paired biopsies from 17 ovarian cancer patients before and after chemotherapy. We reveal that while MRD cells share important molecular signatures with TICs, they are also characterized by an adipocyte-like gene expression signature and a portion of them had undergone epithelial-mesenchymal transition (EMT). In a cell culture MRD model, MRD-mimic cells showed the same phenotype and were dependent on fatty acid oxidation (FAO) for survival and resistance to cytotoxic agents. These findings identify EMT and FAO as attractive targets to eradicate MRD in ovarian cancer and make a compelling case for the further testing of FAO inhibitors in treating MRD.