Abstract
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.
Highlights
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
Considering oxygen is delivered by the bloodstream, it should be noted that hypoxia is accompanied with nutrient starvation in many physiological settings in mammals
Two mTOR complexes. mTOR complex coordinates cell growth and metabolism by integrating growth factor signaling at the nutrient level [46,47]. mTORC exists in two distinct protein kinase complexes. mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of protein synthesis by direct phosphorylation to activate p70 ribosomal protein S6 kinase1 (S6K1) and inactivate eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1)
Summary
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. 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. AMPK is a heterotrimeric protein kinase complex consisting of a catalytic subunit (α1, α2) and two regulatory subunits (β1, β2 and γ1, γ2, γ3), of which the γsubunit functions as an energy sensor by directly binding to adenosine nucleotides, ATP, ADP, or AMP (Figure 1) [3,6].
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