Mitochondrial organization in the developing proximal tubule is controlled by LRRK2

Abstract

The proximal tubule of the nephron resorbs water, amino acids and glucose, and its energy demands are high. Formation of the cellular machinery for energy production is an essential step in proximal tubule epithelial cell (PTC) differentiation, and this report focuses on how mitochondria in nascent PTCs are redistributed from their initial apical position to their ultimate basolateral location. We found that mitochondria move from the apical to basolateral side of the PTC coincident with the initiation of lumen flow and that proximal tubules deficient in filtration (aglomerular mice and kidney organoids) maintain their mitochondria in the apical position, indicating that flow is necessary and sufficient for localization. Further, we show that mitochondrial localization depends on the activity of LRRK2 in vitro and in vivo. Modeling the effect of fluid flow on PTCs demonstrates that LRRK2 activity is regulated by fluid shear stress, providing an explanation for how onset of flow in the newly differentiated proximal tubule may trigger the apical-to-basolateral dissemination of mitochondria that forms the template for subsequent PTC maturation. Our findings indicate that mitochondrial redistribution is one component of a cellular program in the nascent PTC that drives function and that this process is regulated by flow.