Exploring Renal Pyruvate Metabolism as a Therapeutic Avenue for Diabetic Kidney Injury

Pyruvate is a keystone molecule critical for numerous aspects of eukaryotic and human metabolism. Pyruvate is the end-product of glycolysis, is derived from additional sources in the cellular cytoplasm, and is ultimately destined for transport into mitochondria as a master fuel input undergirding citric acid cycle carbon flux. In mitochondria, pyruvate drives ATP production by oxidative phosphorylation and multiple biosynthetic pathways intersecting the citric acid cycle. Mitochondrial pyruvate metabolism is regulated by many enzymes, including the recently discovered mitochondria pyruvate carrier, pyruvate dehydrogenase, and pyruvate carboxylase, to modulate overall pyruvate carbon flux. Mutations in any of the genes encoding for proteins regulating pyruvate metabolism may lead to disease. Numerous cases have been described. Aberrant pyruvate metabolism plays an especially prominent role in cancer, heart failure, and neurodegeneration. Because most major diseases involve aberrant metabolism, understanding and exploiting pyruvate carbon flux may yield novel treatments that enhance human health. Show more

Recent advances have led to a greater appreciation of how mitochondrial dysfunction contributes to diverse acute and chronic pathologies. Indeed, mitochondria have received increasing attention as a therapeutic target in a variety of diseases because they serve as key regulatory hubs uniquely situated at crossroads between multiple cellular processes. This review provides an overview of the role of mitochondrial dysfunction in chronic kidney disease, with special emphasis on its role in the development of diabetic nephropathy. We examine the current understanding of the molecular mechanisms that cause mitochondrial dysfunction in the kidney and describe the impact of mitochondrial damage on kidney function. The new concept that mitochondrial shape and structure are closely linked with its function in the kidneys is discussed. Furthermore, the mechanisms that translate cellular cues and demands into mitochondrial remodeling and cellular damage, including the role of microRNAs and long noncoding RNAs, are examined with the final goal of identifying mitochondrial targets to improve treatment of patients with chronic kidney diseases. Show more

Mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex–dependent mechanism. Excessive MAM formation may cause mitochondrial Ca2+ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that PDK4 interacts with and stabilizes the IP3R1-GRP75-VDAC1 complex at the MAM interface. Obesity-induced increase in PDK4 activity augments MAM formation and suppresses insulin signaling. Conversely, PDK4 inhibition dampens MAM formation and improves insulin signaling by preventing MAM-induced mitochondrial Ca2+ accumulation, mitochondrial dysfunction, and ER stress. Furthermore, Pdk4−/− mice exhibit reduced MAM formation and are protected against diet-induced skeletal muscle insulin resistance. Finally, forced formation and stabilization of MAMs with synthetic ER–mitochondria linker prevented the beneficial effects of PDK4 deficiency on insulin signaling. Overall, our findings demonstrate a critical mediatory role of PDK4 in the development of skeletal muscle insulin resistance via enhancement of MAM formation. Show more