Rac1 promotes proximal tubule kidney repair by coupling the actin cytoskeleton to mitochondrial function
- Olga M. Viquez
- Meiling Melzer
- Shensen Li
- Matthew Tantengco
- Xinyu Dong
- Eric Sha
- Jeffery Huang
- Evan S. Krystofiak
- Rachel C. Hart
- Wentian Luo
- Christian Warren
- Al-Borhan Bayazid
- Richard Zhang
- Ryoichi Bessho
- Volker H. Haase
- Cord Brakebusch
- Takanari Inoue
- Craig Brooks
- Matthew H. Wilson
- Andrew S. Terker
- Juan P. Arroyo
- Ambra Pozzi
- Roy Zent
- Fabian Bock
2025-11-17
The kidney proximal tubule (PT) is a specialized polarized epithelium that functions as a high capacity resorptive machine. PT cells are exquisitely sensitive to ischemia due to their high metabolic rate. The small GTPase Rac1 regulates epithelial function by promoting polarity through its effects on the actin cytoskeleton. We show that Rac1, in the setting of the recovery of the PT from ischemic injury, plays a critical role in reconstituting cellular bioenergetics by promoting actin cytoskeleton formation around damaged mitochondria. This mechanism removes damaged mitochondria through mitophagy and preserves PT metabolic capacity and reabsorption function. Loss of Rac1 causes intracellular lipid accumulation, energy depletion, and PT cell atrophy. Thus, Rac1 promotes the repair of PT cells by enhancing mitochondrial bioenergetics, rather than by regulating cell polarity via a mechanism that links the actin cytoskeleton to metabolic demands and cell morphology.