Abstract
SummaryThe demands of cancer cell proliferation alongside an inadequate angiogenic response lead to insufficient oxygen availability in the tumor microenvironment. Within the mitochondria, oxygen is the major electron acceptor for NADH, with the result that the reducing potential produced through tricarboxylic acid (TCA) cycle activity and mitochondrial respiration are functionally linked. As the oxidizing activity of the TCA cycle is required for efficient synthesis of anabolic precursors, tumoral hypoxia could lead to a cessation of proliferation without another means of correcting the redox imbalance. We show that in hypoxic conditions, mitochondrial pyrroline 5-carboxylate reductase 1 (PYCR1) activity is increased, oxidizing NADH with the synthesis of proline as a by-product. We further show that PYCR1 activity is required for the successful maintenance of hypoxic regions by permitting continued TCA cycle activity, and that its loss leads to significantly increased hypoxia in vivo and in 3D culture, resulting in widespread cell death.
Highlights
Proline is a unique non-essential amino acid with critical roles in both protein structure and the cellular stress response (Phang et al, 2008)
We show that mitochondrial proline synthesis, through pyrroline 5-carboxylate reductase 1 (PYCR1) activity, is essential to support hypoxic metabolism and viability
Hypoxia increases PYCR1-dependent proline synthesis and export from glutamine Our previous research, and that of others, suggested that proline synthesis is increased in cells when cellular redox homeostasis is perturbed or when enhanced oxidation of mitochondrial NADH is required (Hollinshead et al, 2018; McGregor et al, 2020; Schworer et al, 2020)
Summary
Proline is a unique non-essential amino acid with critical roles in both protein structure and the cellular stress response (Phang et al, 2008). Much of the balance of oxidizing and reducing potential within cells is achieved by two pyridine nucleotide couples: NAD+:NADH and NADP+:NADPH. The NAD+:NADH redox couple are of particular importance in linking central carbon metabolism with ATP generation. The mitochondria are major contributors to the overall cellular NAD+/NADH ratio, with the oxidizing activity of the tricarboxylic acid (TCA) cycle driving significant reduction of the mitochondrial NAD+ pool. The high energy electrons from resulting NADH are used to generate the proton gradient across the inner mitochondrial membrane, which generates ATP through oxidative phosphorylation. In conditions of low oxygen (hypoxia) the mitochondrial NADH/NAD+ ratio increases, resulting in fragmentation of the TCA cycle and the need to shuttle reducing potential into the cytosol through the malate-aspartate shuttle (Frezza et al, 2011; LaNoue et al, 1973).
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