# Mitochondrial integrity modulates mTOR signaling and podocyte function

## TL;DR

Mitochondrial health affects kidney cell function and disease, with OMA1 playing a key role in regulating this process.

## Contribution

The study reveals that OMA1 ablation rescues glomerular disease in PHB2-deficient mice.

## Key findings

- OMA1 ablation rescues glomerular disease in PHB2-deficient mice.
- Mitochondrial dysfunction sensitizes podocytes to insulin, triggering mTOR overactivation.
- mTOR hyperactivity alone does not drive glomerular disease.

## Abstract

Mitochondrial dysfunction has emerged as a key contributor to the pathogenesis of steroid-resistant nephrotic syndrome (SRNS) and genetic focal-segmental glomerulosclerosis (FSGS). This study explores the role of mitochondrial integrity in podocyte biology, focusing on the impact of OMA1, a critical regulator of mitochondrial morphology. Using a model of disrupted mitochondrial homeostasis, we show that mitochondrial dysfunction sensitizes podocytes to insulin, triggering the overactivation of mTOR signaling. Disruption of OMA1 function was achieved through the deletion of Oma1 or a podocyte-specific knockout of its regulator Phb2. Remarkably, simultaneous Oma1 deletion extended the lifespan of severely affected Phb2pko mice, alleviated proteinuria, and restored mitochondrial morphology. Increased mTOR activity was observed in Phb2pko, Oma1del, and Phb2/Oma1 double-knockout mice. Our findings highlight the critical role of mitochondrial integrity in podocyte function and disease mitigation, providing potential therapeutic insights for mitochondrial dysfunction-associated nephropathies.

•Oma1 ablation rescues glomerular disease in PHB2-deficient mice•Disruption of mitochondrial dynamics sensitizes podocytes to insulin•mTOR hyperactivity alone does not drive glomerular disease

Oma1 ablation rescues glomerular disease in PHB2-deficient mice

Disruption of mitochondrial dynamics sensitizes podocytes to insulin

mTOR hyperactivity alone does not drive glomerular disease

Cell biology