J Biol Chem. 2023 Jan 7:102881. doi: 10.1016/j.jbc.2023.102881. Online ahead of print.
Mutations in genes involved in mitochondrial proline catabolism lead to the rare genetic disorder hyperprolinemia in humans. We have previously reported that mutations of proline catabolic genes in C. elegans impair mitochondrial homeostasis and shorten lifespan, and that these effects surprisingly occur in a diet type-dependent manner. Therefore, we speculated that a specific dietary component may mitigate the adverse effects of defective proline catabolism. Here, we discovered that high dietary glucose, which is generally detrimental to health, actually improves mitochondrial homeostasis and lifespan in C. elegans with faulty proline catabolism. Mechanistically, defective proline catabolism results in a shift of glucose catabolism towards the pentose phosphate pathway (PPP), which is crucial for cellular redox balance. This shift helps to maintain mitochondrial reactive oxygen species (ROS) homeostasis and to extend lifespan, as suppression of the PPP enzyme GSPD-1 prevents the favorable effects of high glucose. Additionally, we demonstrate that this crosstalk between proline and glucose catabolism is mediated by the transcription factor DAF-16. Altogether, these findings suggest that a glucose-rich diet may be advantageous in certain situations, and might represent a potentially viable treatment strategy for disorders involving impaired proline catabolism.