MCT1 as a critical regulator of insulin signaling, energy homeostasis and podocyte function

TL;DR

This study shows that MCT1 is crucial for podocyte energy balance and function, linking lactate transport to insulin signaling and cell structure.

Contribution

The study reveals MCT1's novel role in regulating podocyte glucose metabolism and cytoskeleton dynamics through lactate transport.

Findings

MCT1 inhibition reduces glucose uptake and glycolytic flux in podocytes.

Blocking MCT1 disrupts insulin signaling and actin cytoskeleton organization.

MCT1 inhibition increases podocyte permeability and shifts metabolism toward oxidative phosphorylation.

Abstract

Podocytes are highly specialized epithelial cells that play a central role in maintaining integrity of the glomerular filtration barrier. Because of their complex architecture and dynamic actin-based cytoskeleton, podocytes have substantial energy requirements, which are predominantly supported by glycolysis. Insulin signaling and glucose uptake are key regulators of cytoskeletal dynamics in these cells. Recent evidence highlights the importance of lactate metabolism in maintaining podocyte metabolic homeostasis, supported by a well-developed system for controlling lactate levels. Monocarboxylate transporter 1 (MCT1), a principal mediator of lactate transport, has emerged as a critical regulator of cellular energy balance. The present study investigated the role of MCT1 in insulin-stimulated glucose metabolism and its impact on podocyte morphology and function. Our findings showed that MCT1 inhibition impaired glucose uptake and suppressed glycolytic flux. This metabolic disruption was accompanied by alterations of the localization of key insulin signaling proteins, disorganization of the actin cytoskeleton, and an increase in permeability of the podocyte layer. Interestingly, MCT1 inhibition also triggered a compensatory shift toward oxidative phosphorylation, potentially linked to an increase in mitochondrial biogenesis. These results underscore the pivotal role of MCT1 in regulating glucose metabolism and actin cytoskeleton organization in podocytes and suggest that lactate transport is essential for preserving their structure and function. Targeting MCT1 and lactate metabolism may offer a novel therapeutic strategy for glomerular diseases that are characterized by insulin resistance and metabolic dysregulation.

The online version contains supplementary material available at 10.1038/s41598-026-37093-x.

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