The Important Role Of Mitochondria in Kidney Homeostasis And Pathogenesis
Mar 22, 2022
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Ken Ishii, Hanako Kobayashi, Kensei Taguchi & et al.
Abnormal mitochondrial function is a well-recognized feature of acute and chronic kidney diseases. To gain insight into the role of mitochondria in kidney homeostasis and pathogenesis, we targeted mitochondrial transcription factor A(TFAM), a protein required for mitochondrial DNA replication and transcription that plays a critical part in the maintenance of mitochondrial mass and function. To examine the consequences of disrupted mitochondrial function in kidney epithelial cells, we inactivated TFAM(targeted mitochondrial transcription factor A) in sine oculis-related homeobox 2-expressing kidney progenitor cells. TFAM(targeted mitochondrial transcription factor A) deficiency resulted in significantly decreased mitochondrial gene expression, mitochondrial depletion, inhibition of nephron maturation, and the development of severe postnatal cystic disease, which resulted in premature death. This was associated with abnormal mitochondrial morphology, a reduction in oxygen consumption, and increased glycolytic flux.
Furthermore, we found that TFAM(targeted mitochondrial transcription factor A) expression was reduced in murine and human polycystic kidneys, which was accompanied by mitochondrial depletion. Thus, our data suggest that dysregulation of TFAM(targeted mitochondrial transcription factor A) expression and mitochondrial depletion are molecular features of kidney cystic disease that may contribute to its pathogenesis.
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DISCUSSION
Here we establish a critical function for mt transcription factor TFAM(targeted mitochondrial transcription factor A) in renal tissue homeostasis. We demonstrate that the inactivation of TFAM(targeted mitochondrial transcription factor A) in SIX2 but not in HOXB7 pro-genitor cells resulted in the development of severe postnatal cystic disease, which was associated with mt depletion and a metabolic shift from OXPHOS toward glycolysis. Furthermore, a decrease in cellular TFAM levels and mt dysfunction are characteristic features of murine and human PKD, suggesting that a reduction in TFAM activity may contribute to and/or modulate the development of renal cystic disease.
Patients with mt disease syndromes are prone to develop kidney pathology. Kidney disease in this setting frequently manifests as tubular dysfunction and/or tubulointerstitial disease, whereas renal cyst formation is rare.2,19-27 Although mutations in TFAM(targeted mitochondrial transcription factor A)-regulated genes, such as MT-CO1," have been identified in patients with the tubulointerstitial disease, mutations in TFAM(targeted mitochondrial transcription factor A) itself have not been reported in patients with chronic kidney disease. Nevertheless, chronic kidney disease progression has been recently associated with decreased TFAM(targeted mitochondrial transcription factor A) activity, which resulted in the activation of fibrotic and inflammatory pathways due to mt stress.42 In contrast to Six2-TFAM(targeted mitochondrial transcription factor A)-7-mutants, mice with Ksp-Cre-mediated TFAM(targeted mitochondrial transcription factor A) inactivation developed renal fibrosis and inflammation but not cystic disease. The phenotypic differences between the 2 models are likely a reflection of which renal cell types were targeted as well as the differentiation state of Cre-expressing cells. Ksp-Cre mediates recombination in the distal nephron with prominent Cre activity in the medullary thick ascending limb of Henle segment and ureteric bud-derived CD,5whereas Six2-eGFP/Cre is expressed in cap mesenchyme and does not target ureteric bud-derived nephron segments.'5Consistent with these findings is the increase in extracellular matrix deposition and absence of cystic disease in 15-month-old Hoxb7-TFAM(targeted mitochondrial transcription factor A)-/-mutants; Hoxb7-Cre targets ureteric bud-derived nephron segments (Supplementary Figure S5). Furthermore, in keeping with the notion of the developmental stage- and cell-type dependence is the observation that inactivation of TFAM(targeted mitochondrial transcription factor A) using Nphs2-Cre(Podocin-Cre) did not result in developmental or adult renal phenotypes, whereas Six2-TFAM(targeted mitochondrial transcription factor A)-7-mice devel-oped significant albuminuria.
Defects in nephron differentiation were not completely unexpected in Six2-TFAM(targeted mitochondrial transcription factor A)-/-mice because cellular differentiation has been associated with increased reliance on OXPHOS for ATP generation, whereas undifferentiated pluripotent cells prefer glycolysis over OXPHOS to meet energy demands.8 To what degree the progressive loss of OXPHOS activity per se contributed to cystogenesis in Six2-TFAM(targeted mitochondrial transcription factor A)-7 mutants warrants further investigation. Recent studies have shown that mutations in PKD1, which are responsible for ～85% of ADPKD cases, are associated with enhanced glycolytic flux. However, the pathophysiologic and therapeutic significance of this finding is not entirely clear because the effects of glucose deprivation on cyst proliferation and PKD progression are controversial,31,32
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Although we do not propose that TFAM(targeted mitochondrial transcription factor A) dysfunction represents a primary event in the development of PKD, our studies raise the possibility that TFAM(targeted mitochondrial transcription factor A) dysfunction may have a contributory role in its pathogenesis and/or progression. We demonstrate that TFAM(targeted mitochondrial transcription factor A) protein levels are reduced in cyst lining epithelial cells from murine and human PKD tissues and found that Six2-TFAM(targeted mitochondrial transcription factor A)-7-tissues share molecular features with PKD tissues that are linked to cystogenesis. Abnormal cilia function has been implicated in the path 29,33,4 Although the absence of genesis of renal cystic diseases., cilia has been reported for some PKD animal models, ilia are formed in Pkd1-/epithelial cells and were also detected in renal cysts from Six2-TFAM(targeted mitochondrial transcription factor A)-/-mice(Supplementary Figure S3). Several signaling pathways linked to cystogenesis are involved in cilia-associated signaling. These include mitogen-activated protein kinase/extracellular signal-regulated kinase signaling and β-catenin-regulated path-ways. Both p-ERK and β-catenin levels were elevated in Sixc2-TFAM(targeted mitochondrial transcription factor A)-7-kidneys, suggesting that these pathways were activated. These findings are consistent with observations made in human ADPKD cells and in several murine PKD models,38-43
Peroxisome proliferator-activated receptor-gamma coactivator 1a. (PGC-1d), an upstream transcriptional regulator of TFAM(targeted mitochondrial transcription factor A) and driver of mt biogenesis was decreased in cell lines isolated from patients with ADPKD and would, in addition to TFAM(targeted mitochondrial transcription factor A) itself, represent a potential therapeutic target for PKD. A reduction in PGC-1o expression has been proposed to promote cyst proliferation due to increased mt superoxide production in PKD1-defective cells. Although we did not measure mt ROS production in our model, tissue-specific TFAM(targeted mitochondrial transcription factor A) inactivation in other cell types was associated with a decrease and not an increase in mt ROS production." In addition to the PGC-1a/TFAM(targeted mitochondrial transcription factor A) axis, recent studies have highlighted a potential role for hypoxia and the hypoxia-inducible factor pathway in the therapy of mt diseases. To what degree hypoxia-associated pathways can be exploited therapeutically for the treatment of diseases that are associated with mt dysfunction, such as PKD, requires further investigation.
In summary, our data demonstrate that mt transcription factor TFAM(targeted mitochondrial transcription factor A) is required for normal nephron differentiation and that loss of TFAM(targeted mitochondrial transcription factor A) activity in renal epithelial cells re-produces molecular and metabolic features associated with PKD. Our findings provide a strong rationale for further investigations into the role of my health and function in cystogenesis. We propose that therapeutic strategies that aim at improving my health may be beneficial for the treatment of patients with PKD.
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