Lactate-Dependent Chaperone-Mediated Autophagy Induces Oscillatory Hif-1α Activity Promoting Proliferation of Hypoxic Cells

Abstract

Response to hypoxia is a highly regulated process controlling multiple cell and tissue level functions. However, we still know little about dynamic single cell responses to hypoxic conditions. Here, using fluorescent reporters of hypoxia response factor-1α (HIF-1α) activity, we show that hypoxic responses in individual cells can be highly dynamic and variable across the population. These responses fall into three classes, including oscillatory activity. We identify a molecular mechanism that can account for all three response classes, demonstrating that the oscillations of HIF-1α activity and abundance are controlled by the reactive oxygen species-dependent chaperone-mediated autophagy in a respiring subset of cells. Furthermore, we find that the oscillatory response is modulated by the abundance of extracellular lactate in a quorum sensing-like mechanism. We show that oscillatory HIF-1α activity can help rescue hypoxia-mediated inhibition of cell division, suggesting a mechanism for aggressive behavior in a subset of hypoxic tumor cells.