Mitochondrial DNA deletion-dependent podocyte injuries in Mito-miceΔ, a murine model of mitochondrial disease
Shuzo Kaneko1, Joichi Usui1, Masahiro Hagiwara1,2
1Department of Nephrology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan.
Abstract:
Focal segmental glomerulosclerosis (FSGS) is a major renal complication of human mitochondrial disease. However, its pathogenesis has not been fully explained. In this study, we focused on the glomerular injury of mito-miceΔ and investigated the pathogenesis of their renal involvement. We analyzed biochemical data and histology in mito-miceΔ. The proteinuria began to show in some mito-miceΔ with around 80% of mitochondrial DNA deletion, then proteinuria developed dependent with higher mitochondrial DNA deletion, more than 90% deletion. Mito-miceΔ with proteinuria histologically revealed FSGS. Immunohistochemistry demonstrated extensive distal tubular casts due to abundant glomerular proteinuria. Additionally, the loss of podocyte-related protein and podocyte's number were found. Therefore, the podocyte injuries and its depletion had a temporal relationship with the development of proteinuria. This study suggested mitochondrial DNA deletion-dependent podocyte injuries as the pathogenesis of renal involvement in mito-miceΔ. The podocytes are the main target of mitochondrial dysfunction originated from the accumulation of mitochondrial DNA abnormality in the kidney.
Insights
Mitochondrial DNA deletion causes kidney damage, specifically focal segmental glomerulosclerosis (FSGS), by injuring podocytes. This damage is directly linked to the extent of mitochondrial DNA deletion in the kidneys.
Area of Science:
- Nephrology
- Mitochondrial Biology
- Genetics
Background:
- Focal segmental glomerulosclerosis (FSGS) is a significant kidney complication in human mitochondrial diseases.
- The precise pathogenesis of FSGS in mitochondrial disease remains incompletely understood.
Purpose of the Study:
- To investigate the pathogenesis of glomerular injury in mice with mitochondrial DNA deletion (mito-miceΔ).
- To elucidate the role of mitochondrial dysfunction in the development of renal pathology.
Main Methods:
- Analysis of biochemical data and kidney histology in mito-miceΔ.
- Histological examination and immunohistochemistry to assess glomerular and tubular damage.
- Evaluation of podocyte-related protein expression and podocyte numbers.
Main Results:
- Proteinuria emerged in mito-miceΔ with approximately 80% mitochondrial DNA deletion, worsening with >90% deletion.
- Histological analysis revealed FSGS in proteinuric mito-miceΔ.
- Extensive distal tubular casts and a reduction in podocyte number and related proteins were observed, correlating with proteinuria.
Conclusions:
- Mitochondrial DNA deletion-induced podocyte injury is the primary mechanism of renal involvement in mito-miceΔ.
- Podocytes are the main targets of kidney mitochondrial dysfunction stemming from abnormal mitochondrial DNA accumulation.
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