Mitochondrial integrity modulates mTOR signaling and podocyte function

Authors:

Cem Özel, Khawla Abualia, Duc Nguyen-Minh, Mahsa Matin, David Unnersjö-Jess, Martin Höhne, Wilhelm Bloch, Henning Hagmann, Richard J. M. Coward, Sebastian Brähler, Bernhard Schermer, Thomas Benzing, Philipp Antczak, Paul T. Brinkkötter

Keywords:

OMA1, phb2, mitochondria, mitochondrial dynamics, podocyte, mitochondrial morphology, mTOR

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 Phb2^pko mice, alleviated proteinuria, and restored mitochondrial morphology. Increased mTOR activity was observed in Phb2^pko, Oma1^del, 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.

< Back to publications

Full article >