Mitochondrial integrity modulates mTOR signaling and podocyte function

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 <i>Oma1</i> or a podocyte-specific knockout of its regulator <i>Phb2</i>. Remarkably, simultaneous <i>Oma1</i> deletion extended the lifespan of severely affected <i>Phb2</i> ^pko mice, alleviated proteinuria, and restored mitochondrial morphology. Increased mTOR activity was observed in <i>Phb2</i> ^<i>pko</i> , <i>Oma1</i> ^<i>del</i> , and <i>Phb2/Oma1</i> 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.