Abstract
Recent studies have implicated mitochondrial disruption in podocyte dysfunction, which is a characteristic feature of primary and diabetic glomerular diseases. However, the mechanisms by which primary mitochondrial dysfunction in podocytes affects glomerular renal diseases are currently unknown. To investigate the role of mitochondrial oxidative phosphorylation (OxPhos) in podocyte dysfunction, glomerular function was examined in mice carrying a loss of function mutation of the gene encoding CR6-interacting factor-1 (CRIF1), which is essential for intramitochondrial production and the subsequent insertion of OxPhos polypeptides into the inner mitochondrial membrane. Homozygotic deficiency of CRIF1 in podocytes resulted in profound and progressive albuminuria from 3 weeks of age; the CRIF1-deficient mice also developed glomerular and tubulointerstitial lesions by 10 weeks of age. Furthermore, marked glomerular sclerosis and interstitial fibrosis were observed in homozygous CRIF1-deficient mice at 20 weeks of age. In cultured mouse podocytes, loss of CRIF1 resulted in OxPhos dysfunction and marked loss or abnormal aggregation of F-actin. These findings indicate that the OxPhos status determines the integrity of podocytes and their ability to maintain a tight barrier and control albuminuria. Analyses of the glomerular function of the podocyte-specific primary OxPhos dysfunction model mice demonstrate a link between podocyte mitochondrial dysfunction, progressive glomerular sclerosis, and tubulointerstitial diseases.
Highlights
Mitochondria are essential intracellular organelles that have a major role in energy production via ATP synthesis [1,2]
CRIF1flox/flox mice were crossed with podocin-Cre mice, in which Cre-recombinase expression is directed to podocytes starting from the capillary loop stage during glomerular development [16]
All CRIF1ctrl mice survived up to 80 weeks, whereas the survival rate of the CRIF1pdKO mice dropped after 25 weeks of age and all CRIF1pdKO mice died within approximately 38 weeks (Figure 1c)
Summary
Mitochondria are essential intracellular organelles that have a major role in energy production via ATP synthesis [1,2]. Patients with mitochondrial dysfunction caused by inherited mutations of mitochondrial DNA (mtDNA) display renal manifestations such as proteinuria and glomerular sclerosis [3,4,5]. Podocytes are specialized epithelial cells that maintain the critical glomerular filtration barrier [6,7] and their dysfunction is frequently associated with glomerular proteinuria, which leads to end-stage renal disease [8]. Patients with mtDNA mutations develop renal diseases with characteristic glomerular sclerosis [11], it is unclear how mitochondrial dysfunction in the kidney leads to glomerular diseases. CRIF1 plays an essential role in mitochondrial synthesis and membrane integration of OxPhos polypeptides [13]. To investigate the renal manifestation of mitochondrial dysfunction, we developed mice with podocyte-specific mitochondrial OxPhos dysfunction by deleting.
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