Kidney Week

Abstract: TH-OR002

Persistent Injury-Induced Mitochondrial DNA Variants Compromise Kidney Function by Suppressing Nucleotide Biosynthesis

Session Information

• AKI Progression and Resolution: Cellular and Molecular Insights
  November 06, 2025 | Location: Room 320A, Convention Center
  Abstract Time: 04:40 PM - 04:50 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Huang, Huihui, Beth Israel Lahey Health Inc, Boston, Massachusetts, United States

Huihui Huang, PhD

• Zsengeller, Zsuzsanna Kinga, Beth Israel Lahey Health Inc, Boston, Massachusetts, United States

Zsuzsanna Kinga Zsengeller, MD, PhD

• Clark, Amanda J., The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Amanda J. Clark, MD

• Parikh, Samir M., The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Samir M. Parikh, MD, FASN

Background

Mitochondrial function is emerging as a critical factor for AKI to CKD progression. Mitochondrial fitness is governed by its own genome, mitochondrial DNA (mtDNA), in harmony with nuclear DNA (ncDNA), which encodes thousands of proteins that are imported into mitochondria. Given the similarity of CKD progression to aging, and the implication of mtDNA mutation accumulation in aging, we hypothesize that acquired de novo mtDNA mutation in acute injury might contribute to AKI-CKD transition.

Methods

Two distinct AKI to CKD transition models have been established, including ischemia-reperfusion injury (IRI) and folic acid (FA)-induced kidney injury models to study the contribution of mtDNA mutation during this process. Human CKD kidney biopsy was employed in this study to determine mtDNA mutation burden via next-generation sequencing. Functional studies utilized CRISPR knock-in mtDNA mutator cell lines Polg ^D257A+/− and Polg ^D257A mutator mice. Multi-omics, including bulk-RNA seq, metabolomics, and single-nucleus RNA-seq (snRNA-seq), were leveraged to uncover underlying mechanisms of mtDNA mutation-induced AKI to CKD transition.

Results

Both IRI and FA-induced injury provoke the development of persistent random mtDNA mutations in the mouse kidney. Human kidney biopsy exhibited a proportional relationship between mtDNA mutation burden and physiological impairment. Polg ^D257A(+/-) cells showed more ATP depletion and fibrotic gene expression after H₂O₂ stimulation. Polg ^D257A mice developed more severe kidney injury and subsequently more fibrosis after IRI and FA-induced kidney injury.

Mechanistically, multi-omics analyses showed that mtDNA mutations induced a deficiency of purine biosynthesis. Supplementation with adenosine through the adenosine-AMP-ADP-ATP pathway via a nuDNA coded protein adenylate kinase 4(AK4) significantly alleviated mtDNA mutation-induced cell death and kidney injury, subsequently fibrosis development.

Conclusion

Transient injury results in persistent mtDNA mutation, which compromises kidney function to future insults, resulting in a destructive feed-forward loop. Purine metabolism buffers the deleterious effects of mtDNA mutation. The nuclear-encoded mitochondrial protein AK4 may serve as a nuclear genetic control of mitochondrial genome mutation.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025sq5x8b0h