Free Mitochondrial DNA and Mitophagy Dysfunction in Diabetic Kidney Disease: A Central Mitochondrial-Inflammatory Axis Driving Progressive Renal Injury.
7 affiliations
- 1Department of Translational Research, Temple University, Philadelphia, PA 19140, USA.
- 2Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.
- 3Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH 43205, USA.
- 4The Heart Center, Nationwide Children's Hospital, Columbus, OH 43205, USA.
- 5Center for Inflammation and Lung Research, Temple University, Philadelphia, PA 19140, USA.
- 6Department of Nephrology, Hypertension & Kidney Transplantation, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
- 7Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA.
Abstract
Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease and end-stage renal failure worldwide despite significant advances in glucose-lowering and renoprotective therapies. Emerging evidence identifies mitochondrial dysfunction as a central pathogenic mechanism linking metabolic stress to chronic inflammation and progressive renal injury. In the diabetic kidney, hyperglycemia, lipotoxicity, and oxidative stress impair mitochondrial quality control pathways, particularly mitophagy, a targeted mitochondrial degradation pathway, leading to the accumulation of dysfunctional mitochondria and increased mitochondrial reactive oxygen species production. A critical consequence of mitochondrial damage is the cytosolic release of mitochondrial DNA (mtDNA), which acts as a potent damage-associated molecular pattern and can activate innate immune pathways, including cGAS-STING, NLRP3 inflammasome, and Toll-like receptor 9 signaling. Persistent mtDNA-driven immune activation promotes sterile inflammation, cellular senescence, extracellular matrix remodeling, and renal fibrosis, thereby establishing a vicious cycle that accelerates DKD progression. In this review, we examine the emerging role of the mitochondrial DNA-inflammatory axis in DKD, highlighting the interplay between mitophagy dysfunction, mtDNA release, innate immune activation, and fibrotic remodeling. We further discuss the potential of circulating and urinary mtDNA as biomarkers of disease activity and evaluate therapeutic strategies targeting mitochondrial quality control, oxidative stress, and mtDNA-sensing pathways. Collectively, these findings position mtDNA as a critical mechanistic link between mitochondrial dysfunction and chronic inflammation, and support targeting the mitochondrial-immune axis as a promising strategy for precision therapies in DKD.
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BibTeX
@article{das2026free,
title = {{Free Mitochondrial DNA and Mitophagy Dysfunction in Diabetic Kidney Disease: A Central Mitochondrial-Inflammatory Axis Driving Progressive Renal Injury.}},
author = {Aasthika Das and Eric Lalu and Vikky Awasthi and Cyrine Ben Dhaou and Hebaalaha Hussein and Glenn Gerhard and Karim Bahmed and Iris Lee and Vishwajeet Puri and Rihab Bouchareb},
journal = {Cells},
year = {2026},
month = sep,
doi = {10.3390/cells15191746},
url = {https://europepmc.org/article/MED/42882444},
note = {CC BY},
}
RIS
TY - JOUR
TI - Free Mitochondrial DNA and Mitophagy Dysfunction in Diabetic Kidney Disease: A Central Mitochondrial-Inflammatory Axis Driving Progressive Renal Injury.
AU - Aasthika Das
AU - Eric Lalu
AU - Vikky Awasthi
AU - Cyrine Ben Dhaou
AU - Hebaalaha Hussein
AU - Glenn Gerhard
AU - Karim Bahmed
AU - Iris Lee
AU - Vishwajeet Puri
AU - Rihab Bouchareb
PY - 2026
DA - 2026/09/24
JO - Cells
DO - 10.3390/cells15191746
UR - https://europepmc.org/article/MED/42882444
AB - Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease and end-stage renal failure worldwide despite significant advances in glucose-lowering and renoprotective therapies. Emerging evidence identifies mitochondrial dysfunction as a central pathogenic mechanism linking metabolic stress to chronic inflammation and progressive renal injury. In the diabetic kidney, hyperglycemia, lipotoxicity, and oxidative stress impair mitochondrial quality control pathways, particularly mitophagy, a targeted mitochondrial degradation pathway, leading to the accumulation of dysfunctional mitochondria and increased mitochondrial reactive oxygen species production. A critical consequence of mitochondrial damage is the cytosolic release of mitochondrial DNA (mtDNA), which acts as a potent damage-associated molecular pattern and can activate innate immune pathways, including cGAS-STING, NLRP3 inflammasome, and Toll-like receptor 9 signaling. Persistent mtDNA-driven immune activation promotes sterile inflammation, cellular senescence, extracellular matrix remodeling, and renal fibrosis, thereby establishing a vicious cycle that accelerates DKD progression. In this review, we examine the emerging role of the mitochondrial DNA-inflammatory axis in DKD, highlighting the interplay between mitophagy dysfunction, mtDNA release, innate immune activation, and fibrotic remodeling. We further discuss the potential of circulating and urinary mtDNA as biomarkers of disease activity and evaluate therapeutic strategies targeting mitochondrial quality control, oxidative stress, and mtDNA-sensing pathways. Collectively, these findings position mtDNA as a critical mechanistic link between mitochondrial dysfunction and chronic inflammation, and support targeting the mitochondrial-immune axis as a promising strategy for precision therapies in DKD.
SN - 2073-4409
ER -