TY - JOUR
T1 - Mitochondrial Integrity Modulates mTOR Signaling and Podocyte Function
AU - Özel, Cem
AU - Abualia, Khawla
AU - Nguyen-Minh, Duc
AU - Matin, Mahsa
AU - Unnersjö-Jess, David
AU - Höhne, Martin
AU - Bloch, Wilhelm
AU - Hagmann, Henning
AU - Coward, Richard J.M.
AU - Brähler, Sebastian
AU - Schermer, Bernhard
AU - Benzing, Thomas
AU - Antczak, Philipp
AU - Brinkkötter, Paul T.
N1 - Publisher Copyright:
© 2025 The Author(s)
PY - 2026/1/16
Y1 - 2026/1/16
N2 - 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 overactivation of mTOR signaling. Disruption of OMA1 function was achieved through 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.
AB - 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 overactivation of mTOR signaling. Disruption of OMA1 function was achieved through 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.
U2 - 10.1016/j.isci.2025.114279
DO - 10.1016/j.isci.2025.114279
M3 - Article (Academic Journal)
C2 - 41509918
SN - 2589-0042
VL - 29
JO - iScience
JF - iScience
IS - 1
M1 - 114279
ER -