Ampk–mtor signaling and cellular adaptations in hypoxia

Cellular energy is primarily provided by the oxidative degradation of nutrients coupled with mitochondrial respiration, in which oxygen participates in the mitochondrial electron transport chain to enable electron flow through the chain complex (I–IV), leading to ATP production. Therefore, oxygen supply is an indispensable chapter in intracellular bioenergetics. In mammals, oxygen is delivered by the bloodstream. Accordingly, the decrease in cellular oxygen level (hypoxia) is accompanied by nutrient starvation, thereby integrating hypoxic signaling and nutrient signaling at the cellular level. Importantly, hypoxia profoundly affects cellular metabolism and many relevant physiological reactions induce cellular adaptations of hypoxia-inducible gene expression, metabolism, reactive oxygen species, and autophagy. Here, we introduce the current knowledge of hypoxia signaling with two-well known cellular energy and nutrient sensing pathways, AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1). Additionally, the molecular crosstalk between hypoxic signaling and AMPK/mTOR pathways in various hypoxic cellular adaptions is discussed. Oxygen (O₂) is a key factor for driving cellular metabolism in mitochondria to maintain cellular energy homeostasis for cell proliferation and growth. Therefore, under low oxygen conditions that do not reach the cellular requirement (hypoxia, 0.5–2% oxygen), vertebrates should reprogram the metabolic pathways and the corresponding regulatory circuits in response to the stressful conditions caused by hypoxia, thereby promoting cell survival [1,2]. Considering oxygen is delivered by the bloodstream, it should be noted that hypoxia is accompanied with nutrient starvation in many physiological settings in mammals. Therefore, it is necessary to consider the crosstalk between hypoxic signaling and nutrient signaling and the consequent metabolic changes. In the nutrient signaling, AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) play an important role in balancing cellular energy homeostasis by sensing cellular ATP and nutrient (glucose and amino acids) levels. They are also key upstream regulators for triggering autophagy, an essential cellular homeostasis program that removes harmful and damaged cellular materials and provides cellular energy sources and building blocks. The AMPK–mTOR pathway cooperates with autophagy to fine-tune metabolic activity in response to stressful conditions. In this review, we will introduce and discuss the current understanding of AMPK–mTOR signaling and cellular adaptations in hypoxia.