Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic
7 affiliations
- 1Department of Radiology, University of Washington, Seattle, Washington, USA
- 2University of Washington
- 3Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
- 4University of Pennsylvania
- 5Department of Genome Sciences, University of Washington, Seattle, Washington, USA
- 6Department of Radiology, University of Washington, Seattle, Washington, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
- 7Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA. Electronic address: [email protected]
Abstract
INTRODUCTION: Whether and how podocytes depend on mitochondria across their long post-mitotic lifespan is unclear. With limited cell numbers and broad kidney distribution, isolation of podocyte mitochondria typically requires first isolating podocytes themselves. Disassociation of podocytes from their basement membrane, however, recapitulates an injured state and stresses mitochondria. Here, we devise a new strategy to examine mitochondria in podocytes. METHODS: To address this, we crossed floxed hemagglutinin (HA)-mitochondria tagged (MITO-Tag) mice with those expressing Cre in either podocytes (NPHS2) or mixed tubules (CDH16), thus allowing for rapid, kidney cell-specific, isolation of mitochondria via immunoprecipitation. RESULTS: Mitochondrial respiration in fresh isolates from young (4-7 months) and aged (22-26 months) mice of both sexes demonstrated several previously unreported significant differences between podocyte and tubule mitochondria. First, although podocytes contain fewer mitochondria than tubule cells, mitochondria isolated from podocytes averaged twice the respiratory capacity of tubule mitochondria when normalized to mitochondrial content by citrate synthase levels. Second, age-related decline in respiration was detected only in podocyte mitochondria and only in aged male mice. Third, disassociating podocytes for cell culture initiates functional decline in mitochondria as those from cultured primary podocytes have half the respiratory capacity, but twice the hydrogen peroxide production, of podocyte mitochondria isolated directly from fresh kidneys. Finally, conformation of electron transport chain proteins differed between podocyte and tubule mitochondria, suggesting that cell-specific mitochondrial protein conformations dictate cell-specific mitochondrial function. CONCLUSIONS: Previous studies suggesting a limited role for mitochondrial regulation of podocytes relied on cell culture. This resulted in artifactual suppression of mitochondrial function and masks the roles of mitochondria in maintenance of podocyte health. Our approach shows that per organelle, podocytes maintain sexually dimorphic mitochondria with greater oxidative phosphorylation capacity than the mitochondria-dependent tubules.
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BibTeX
@article{campbell2026mitochondrial,
title = {{Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic}},
author = {Matthew D. Campbell and Mónica Sánchez-Contreras and Britta D. Sibley and Phoebe Keiser and Carla Ruiz Sanchez and Carolyn N. Mann and Anna A. Bakhtina and James E. Bruce and David Joseph Marcinek and Behzad Najafian and Mariya T. Sweetwyne},
journal = {Kidney International},
year = {2026},
month = may,
doi = {10.1016/j.kint.2026.04.016},
url = {https://doi.org/10.1016/j.kint.2026.04.016},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic
AU - Matthew D. Campbell
AU - Mónica Sánchez-Contreras
AU - Britta D. Sibley
AU - Phoebe Keiser
AU - Carla Ruiz Sanchez
AU - Carolyn N. Mann
AU - Anna A. Bakhtina
AU - James E. Bruce
AU - David Joseph Marcinek
AU - Behzad Najafian
AU - Mariya T. Sweetwyne
PY - 2026
DA - 2026/05/21
JO - Kidney International
DO - 10.1016/j.kint.2026.04.016
UR - https://doi.org/10.1016/j.kint.2026.04.016
AB - INTRODUCTION: Whether and how podocytes depend on mitochondria across their long post-mitotic lifespan is unclear. With limited cell numbers and broad kidney distribution, isolation of podocyte mitochondria typically requires first isolating podocytes themselves. Disassociation of podocytes from their basement membrane, however, recapitulates an injured state and stresses mitochondria. Here, we devise a new strategy to examine mitochondria in podocytes. METHODS: To address this, we crossed floxed hemagglutinin (HA)-mitochondria tagged (MITO-Tag) mice with those expressing Cre in either podocytes (NPHS2) or mixed tubules (CDH16), thus allowing for rapid, kidney cell-specific, isolation of mitochondria via immunoprecipitation. RESULTS: Mitochondrial respiration in fresh isolates from young (4-7 months) and aged (22-26 months) mice of both sexes demonstrated several previously unreported significant differences between podocyte and tubule mitochondria. First, although podocytes contain fewer mitochondria than tubule cells, mitochondria isolated from podocytes averaged twice the respiratory capacity of tubule mitochondria when normalized to mitochondrial content by citrate synthase levels. Second, age-related decline in respiration was detected only in podocyte mitochondria and only in aged male mice. Third, disassociating podocytes for cell culture initiates functional decline in mitochondria as those from cultured primary podocytes have half the respiratory capacity, but twice the hydrogen peroxide production, of podocyte mitochondria isolated directly from fresh kidneys. Finally, conformation of electron transport chain proteins differed between podocyte and tubule mitochondria, suggesting that cell-specific mitochondrial protein conformations dictate cell-specific mitochondrial function. CONCLUSIONS: Previous studies suggesting a limited role for mitochondrial regulation of podocytes relied on cell culture. This resulted in artifactual suppression of mitochondrial function and masks the roles of mitochondria in maintenance of podocyte health. Our approach shows that per organelle, podocytes maintain sexually dimorphic mitochondria with greater oxidative phosphorylation capacity than the mitochondria-dependent tubules.
SN - 0085-2538
SN - 1523-1755
ER -