Kidney Week

Abstract: FR-PO1214

Blockade of Tubule-Specific Mitochondrial Calcium Uniporter (MCU) Augments Renal Fatty Acid Oxidation in High-Fat Diet-Induced Obese Mice

Session Information

• CKD: Mechanisms - 2
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Maity, Soumya, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Soumya Maity, PhD

• Singh, Pragya, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Pragya Singh

• Tamayo, Ian M., The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Ian M. Tamayo, MS

• Saliba, Afaf, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Afaf Saliba, MS, PhD

• Lee, Hak Joo, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Hak Joo Lee, PhD

• Montellano, Richard, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Richard Montellano

• Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Kumar Sharma, MD, FASN

Background

Impaired fatty acid oxidation (FAO) is a consequence of obesity-induced chronic kidney disease. Proximal tubular cells depend on FAO to fulfill their high energy demand. The mitochondrial Ca²⁺ uniporter (MCU) complex mediates acute mitochondrial Ca²⁺ influx to drive mitochondrial bioenergetics. However, loss of Mcu is reported to enhance muscle performance with a preferential shift toward fatty acid metabolism. Here, we examined the role of MCU in renal fatty acid metabolism in a high-fat diet (HFD)-induced obese model.

Methods

8-12 weeks wildtype (WT) and tubule-specific Mcu knock-out (Mcu^fl/fl X Pax8-Cre^+/-; Mcu KO) male mice were fed with HFD for six months. MALDI-MSI followed by untargeted analysis using MetaboAnalyst 6.0 was carried out to evaluate the distribution of lipid species in the kidney cortex. The mitochondrial oxygen consumption rate (OCR) was used as a functional readout of mitochondrial bioenergetics. Histological staining, western blots, and biochemical assays were employed to establish the mechanism.

Results

Loss of MCU did not affect kidney growth and maturation. Histological staining showed a significant decrease in the size and number of lipid droplets in renal tubules of Mcu KO compared to WT mice under HFD stress. Lipid droplet-associated protein perilipin 2 was decreased in HFD Mcu KO mouse kidneys. MSI data demonstrated that kidneys from HFD group accumulated several lipid species, notably different subtypes of phosphatidylcholine and ceramides, in WT tubules. These lipid species were significantly reduced in Mcu KO tubules. Palmitic acid treatment in MCU knockdown human proximal tubular (HK2) cells showed a higher OCR and less lipid accumulation. The upregulation of CPT1 in HFD Mcu KO mice's kidneys suggests that MCU loss facilitates FAO in renal tubules. Moreover, increased L-carnitine and phosphorylation of pyruvate dehydrogenase α1 at ser-293 in kidneys of Mcu KO mice with regular diet indicate that renal tubules undergo metabolic reprogramming towards favorable FAO in absence of MCU to combat lipid stress.

Conclusion

Loss of MCU promotes fatty acid oxidation in kidney tubules and reduces renal lipid accumulation in high-fat diet stress. These findings open possibilities for treating obesity-induced lipotoxicity in the kidney by tubule-specific MCU inhibition.

Funding

• NIDDK Support