Related Experiment Video
Updated: Feb 26, 2026
Modeling Hypoxia/Reoxygenation Injury in Proximal Tubular Epithelial Cells
Published on: November 21, 2025
Discoidin Domain Receptor 1 Translocation to the Mitochondria Promotes Oxidative Stress and Apoptosis in Acute Kidney
Gema Bolas1, Corina M Borza1, Fabian Bock1
1Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Key Points:
Discoidin domain receptor 1 (DDR1) translocated to the mitochondria of proximal tubule cells after AKI. DDR1 contributed to AKI by promoting the production of mitochondrial reactive oxygen species and cell apoptosis. Mechanistically, DDR1 translocated to mitochondria by interacting with Hsp60 and promoted oxidative stress by regulating phosphorylation of p66Shc.
Background:
Mitochondrial damage with overproduction of mitochondrial reactive oxygen species (mtROS) and apoptosis is a hallmark of AKI. Discoidin domain receptor 1 (DDR1) is a collagen receptor tyrosine kinase that contributes to AKI. Mass spectrometry analysis of DDR1-interacting proteins identified several mitochondrial proteins, suggesting that DDR1 associated with mitochondria. Thus, we analyzed whether DDR1 translocated to mitochondria and promoted mitochondrial dysfunction after AKI.
Methods:
We analyzed DDR1 localization in kidneys of patients with AKI and mice after ischemia/reperfusion-induced AKI. To determine whether mitochondrial DDR1 (mtDDR1) regulated mitochondrial functions, we generated kidney cells expressing wild-type or a kinase dead DDR1. Then, we investigated the location of wild-type or mutated DDR1 on collagen stimulation, the steps involved in DDR1 mitochondrial translocation, and the contribution of mtDDR1 in regulating mtROS production and apoptosis.
Results:
mtDDR1 was detected in injured human and mice kidneys, and collagen-activated DDR1 translocated to the mitochondria where it increased mtROS production and tubule cell apoptosis. Collagen-activated DDR1 translocated to the outer membrane of mitochondria through its association with the chaperone mtHsp60 and induced oxidative stress and apoptosis by promoting tyrosine phosphorylation of p66Shc, a regulator of the cellular redox state and apoptosis. Moreover, cells expressing a kinase dead DDR1, treated with a DDR1 inhibitor, or expressing p66Shc mutated in the DDR1-targeted phosphorylation sites had reduced mtROS and apoptosis.
Conclusions:
We describe a novel noncanonical pathway whereby activated DDR1 translocates to the mitochondria to promote oxidative stress and cell apoptosis.
Insights
Discoidin Domain Receptor 1 (DDR1) moves to mitochondria in acute kidney injury (AKI), increasing mitochondrial reactive oxygen species (mtROS) and apoptosis. Inhibiting DDR1 or its downstream effects reduces kidney injury.
Area of Science:
- Nephrology
- Cell Biology
- Biochemistry
Background:
- Acute kidney injury (AKI) is characterized by mitochondrial damage and increased mitochondrial reactive oxygen species (mtROS).
- Discoidin Domain Receptor 1 (DDR1), a collagen receptor tyrosine kinase, plays a role in AKI.
- DDR1 has been found to interact with mitochondrial proteins, suggesting a mitochondrial role.
Purpose of the Study:
- To investigate whether DDR1 translocates to mitochondria in AKI.
- To determine if mitochondrial DDR1 (mitDDR1) contributes to mitochondrial dysfunction, mtROS production, and apoptosis in AKI.
Main Methods:
- DDR1 localization was analyzed in human and mouse kidneys with AKI.
- Kidney cells expressing wild-type or kinase-dead DDR1 were used to study DDR1 translocation and function.
- The role of mitDDR1 in regulating mtROS and apoptosis was assessed, including its interaction with mtHsp60 and p66Shc phosphorylation.
Main Results:
- mitDDR1 was detected in injured kidneys from human patients and mice.
- Collagen-activated DDR1 translocated to mitochondria, increasing mtROS production and tubule cell apoptosis.
- This translocation involved association with mtHsp60 and promoted p66Shc phosphorylation, leading to oxidative stress and apoptosis. Inhibition of DDR1 or p66Shc phosphorylation reduced these effects.
Conclusions:
- Activated DDR1 translocates to mitochondria via a novel non-canonical pathway.
- This mitochondrial translocation promotes oxidative stress and apoptosis, contributing to AKI pathogenesis.
- Targeting this DDR1 pathway may offer therapeutic strategies for AKI.
Related Concept Videos
01:29Acute Kidney Injury II: Pathophysiology
01:31The Intrinsic Apoptotic Pathway
01:22Acute Kidney Injury I: Introduction
01:31Regulation of the Unfolded Protein Response
01:30Acute Kidney Injury IV: Diagnostic Studies and Prevention
01:17The Extrinsic Apoptotic Pathway