DHODH inhibition modulates glucose metabolism and circulating GDF15, and improves metabolic balance

Abstract

Dihydroorotate dehydrogenase (DHODH) is essential for the de novo synthesis of pyrimidine ribonucleotides, and as such, its inhibitors have been long used to treat autoimmune diseases and are in clinical trials for cancer and viral infections. Interestingly, DHODH is located in the inner mitochondrial membrane and contributes to provide ubiquinol to the respiratory chain. Thus, DHODH provides the link between nucleotide metabolism and mitochondrial function. Here we show that pharmacological inhibition of DHODH reduces mitochondrial respiration, promotes glycolysis, and enhances GLUT4 translocation to the cytoplasmic membrane and that by activating tumor suppressor p53, increases the expression of GDF15, a cytokine that reduces appetite and prolongs lifespan. In addition, similar to the antidiabetic drug metformin, we observed that in db/db mice, DHODH inhibitors elevate levels of circulating GDF15 and reduce food intake. Further analysis using this model for obesity-induced diabetes revealed that DHODH inhibitors delay pancreatic b cell death and improve metabolic balance.

SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with diabetic kidney disease

“…A previous study described kidney-specific metabolic reprogramming associated with mitochondrial dysfunctional in db/db mice, manifesting as a compensatory increase in glycolysis and fatty acid metabolism, which was a response to diminished production of ATP induced by dysfunction of the mitochondrial electron transport chain and uncoupling of oxidative phosphorylation [ 69 ]. Dihydroorotate dehydrogenase (DHODH) is the first rate-limiting enzyme of pyrimidine de novo synthesis, catalyzing the dihydroorotate oxidized to orotate and further producing various downstream pyrimidine nucleotides [ 70 ]. DHODH delivers electrons to ubiquinone during this process and provides reductive ubiquinone for compounds I and III of the respiratory chain, thus coupling the pyrimidine metabolism with mitochondrial phosphorylation [ 71 ].…”

The Role of GDF15 as a Myomitokine

“…Gene expression of Gdf15 has been shown to be regulated by p53 [ 63 ], as well as CHOP [ 4 , 31 , 32 ]. While p53-mediated transcription of Gdf15 is induced in response to several stressors, such as hypoxia and inflammation [ 62 , 64 ], CHOP is induced through the mitochondrial unfolded protein response (UPRmt) and the final effector of the ISR, as already mentioned. In cardiomyocytes, Gdf15 expression seems to be induced by nitric oxide signaling, as well as IL1-β/IFN-γ [ 65 ].…”

The mitochondrial coenzyme Q junction and complex III: biochemistry and pathophysiology

“…Compromised CoQ oxidation can inhibit DHODH, but some evidence suggests that DHODH inhibition can also cause mitochondrial dysfunction on its own [116,120,121]. Interestingly, DHODH inhibition is sufficient to induce the expression of GDF15 [122], one of the best circulating markers of mitochondrial dysfunction [123]. biosynthetic route explains some of the mitochondrial dysfunction-related tissue phenotypes remains poorly understood.…”