Mitochondrial Fatty Acid Oxidation
The kidney’s proximal tubule cells, targets of injury, preferentially use fatty acid oxidation to generate the high amount of ATP needed to support their reabsorptive functions. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for fatty acid oxidation (FAO). To better understand the role of mitochondrial FAO in injury, we have selectively deleted CPT1A in kidney tubules. We recently published data showing that these mice unexpectedly had modest changes in aging and no difference in chronic injury compared to floxed controls. Data suggests that increased peroxisomal FAO activity may be compensating for the loss of CPT1A, indicating a robust alternative pathway for fatty acid metabolism. These findings suggest that peroxisomal β-oxidation could play a crucial role when mitochondrial FAO is impaired.
Peroxisomal Fatty Acid Oxidation
ACOX1 is the key rate limiting enzyme for fatty acid oxidation in peroxisomes. The proximal tubule preferentially uses fatty acid oxidation to generate the ATP to support its high metabolic demands. Mitochondria are critical to fatty acid oxidation, but the peroxisomes can also oxidize fatty acids and likely interact with the mitochondria to regulate oxidative metabolism in the proximal tubules. Peroxisomes are also the only organelle to metabolize very long chain fatty acids (VLCFA), and unmetabolized VLCFA may be injurious to proximal tubules. We are interested in understanding the role of ACOX1 and peroxisomal fatty acid oxidation in acute and chronic kidney injury and delineating how peroxisomal metabolism interacts with mitochondrial oxidation.
Glucose and Pyruvate Metabolism
The Gewin lab collaborates with Brian Finck, PhD, to study the mitochondrial pyruvate carrier (MPC) in the kidney tubules and how its inhibition affects injury and aging. The MPC is the central regulator of glucose/pyruvate metabolism as it controls pyruvate movement into the mitochondrial. Thus, it is essential for glucose/pyruvate oxidation and gluconeogenesis. We are using conditional genetic deletions of Mpc2 in the kidney tubules and well-established inhibitors, tested in phase 2 clinical trials, to assess the role in kidney injury and aging.
FOXO3 Project
FOXO3 is a highly pleiotropic transcription factor involved in cell division, apoptosis, and energy sensing. Prior research by the Gewin Lab showed that beta-catenin binds with FOXO3 in chronic kidney disease and states of oxidative stress. Cystathionine gamma-lyase (Cth) was identified as a downstream target of the FOXO3/beta-catenin pathway. Cth encodes for hydrogen sulfide with known antioxidant effects. Currently, we are investigating the role of tubular FOXO3 in acute kidney injury using a conditional genetic deletion of FOXO3 in the proximal tubule.
Cell Cycle Project
Patients with chronic kidney disease (CKD) have transcriptomic changes consistent with increased cell cycle in the proximal tubules compared with patients lacking CKD. However, whether cell cycle progression is adaptive or maladaptive may depend upon the timing relative to injury. We recently reported that inhibiting cyclin-dependent kinases 4/6 (CDK4/6) with the FDA-approved drug palbociclib is protective in chronic kidney disease, but the mechanisms are not completely clear. Cell cycle is closely tied to regulation of metabolism, and we are investigating whether these metabolic changes may be mediating the protective effect of palbociclib in the context of CKD.