Increased mitochondrial fragmentation in polycystic kidney disease acts as a modifier of disease progression

Cassina, Laura; Chiaravalli, Marco; Boletta, Alessandra

doi:10.1096/fj.201901739rr

Cited by 40 publications

(35 citation statements)

References 34 publications

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“…Mdivi-1 also has been tested in CKD models; however, Mdivi-1 treatment seems to exhibit divergent functions in different studies. In Ksp-Cre;Pkd1 flox/- mice, administration of Mdivi-1 significantly reduced kidney/body weight, cyst formation, and improved renal function by interfering with Drp1 and rescuing mitochondrial fragmentation [ 101 ]. In UUO model, treatment with Mdivi-1 decreased mitochondrial PTEN-induced putative kinase 1 (PINK1), parkin RBR E3 ubiquitin protein ligase (PARK2), and LC3II levels; increased mtROS production; and worsened renal fibrosis following UUO [ 102 ], which suggested that Drp1-regulated PARK2-dependent mitophagy plays a protective role in kidney following injury.…”

Section: Mitochondrial Targeting For Aki and Ckd Therapymentioning

confidence: 99%

The Role of Mitochondria in Acute Kidney Injury and Chronic Kidney Disease and Its Therapeutic Potential

Zhang

Agborbesong

2021

IJMS

107

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Mitochondria are heterogeneous and highly dynamic organelles, playing critical roles in adenosine triphosphate (ATP) synthesis, metabolic modulation, reactive oxygen species (ROS) generation, and cell differentiation and death. Mitochondrial dysfunction has been recognized as a contributor in many diseases. The kidney is an organ enriched in mitochondria and with high energy demand in the human body. Recent studies have been focusing on how mitochondrial dysfunction contributes to the pathogenesis of different forms of kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD). AKI has been linked to an increased risk of developing CKD. AKI and CKD have a broad clinical syndrome and a substantial impact on morbidity and mortality, encompassing various etiologies and representing important challenges for global public health. Renal mitochondrial disorders are a common feature of diverse forms of AKI and CKD, which result from defects in mitochondrial structure, dynamics, and biogenesis as well as crosstalk of mitochondria with other organelles. Persistent dysregulation of mitochondrial homeostasis in AKI and CKD affects diverse cellular pathways, leading to an increase in renal microvascular loss, oxidative stress, apoptosis, and eventually renal failure. It is important to understand the cellular and molecular events that govern mitochondria functions and pathophysiology in AKI and CKD, which should facilitate the development of novel therapeutic strategies. This review provides an overview of the molecular insights of the mitochondria and the specific pathogenic mechanisms of mitochondrial dysfunction in the progression of AKI, CKD, and AKI to CKD transition. We also discuss the possible beneficial effects of mitochondrial-targeted therapeutic agents for the treatment of mitochondrial dysfunction-mediated AKI and CKD, which may translate into therapeutic options to ameliorate renal injury and delay the progression of these kidney diseases.

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Section: Mitochondrial Targeting For Aki and Ckd Therapymentioning

confidence: 99%

The Role of Mitochondria in Acute Kidney Injury and Chronic Kidney Disease and Its Therapeutic Potential

Zhang

Agborbesong

2021

IJMS

107

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“…Evidence suggests that the cystic epithelial lining shares neoplastic features (Rowe et al, 2013). Impaired mitochondrial structure and function play a role in ADPKD disease progression (Cassina et al, 2020). Metabolic reprogramming in PKD is similar to that reported in cancer (Rowe et al, 2013).…”

Section: Metabolic and Mitochondrial Reprogramming In Polycystic Kidnmentioning

confidence: 70%

Loss of Mitochondrial Control Impacts Renal Health

2020

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Disruption of mitochondrial biosynthesis or dynamics, or loss of control over mitochondrial regulation leads to a significant alteration in fuel preference and metabolic shifts that potentially affect the health of kidney cells. Mitochondria regulate metabolic networks which affect multiple cellular processes. Indeed, mitochondria have established themselves as therapeutic targets in several diseases. The importance of mitochondria in regulating the pathogenesis of several diseases has been recognized, however, there is limited understanding of mitochondrial biology in the kidney. This review provides an overview of mitochondrial dysfunction in kidney diseases. We describe the importance of mitochondria and mitochondrial sirtuins in the regulation of renal metabolic shifts in diverse cells types, and review this loss of control leads to increased cell-to-cell transdifferentiation processes and myofibroblast-metabolic shifts, which affect the pathophysiology of several kidney diseases. In addition, we examine mitochondrial-targeted therapeutic agents that offer potential leads in combating kidney diseases.

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“…Given the therapeutic potential of this approach, we have sought to determine the mechanisms responsible for producing the altered cellular metabolic state. A number of recent studies have focused on the mitochondrion, with multiple groups reporting structural and functional abnormalities in cells and tissues of Pkd1 mutants [4–7, 42]. We and others have also described direct physical and functional links between PC1 and mitochondria[6, 7, 42].…”

Section: Discussionmentioning

confidence: 99%

Pkd1mutation has no apparent effects on peroxisome structure or lipid metabolism

Terabayashi

Menezes

Zhou

et al. 2021

Preprint

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Background: Multiple studies of tissue and cell samples from patients and pre-clinical models of autosomal dominant polycystic kidney disease report abnormal mitochondrial function and morphology and suggest metabolic reprogramming is an intrinsic feature of this disease. Peroxisomes interact with mitochondria physically and functionally, and congenital peroxisome biogenesis disorders can cause various phenotypes, including mitochondrial defects, metabolic abnormalities and renal cysts. We hypothesized that a peroxisomal defect might contribute to the metabolic and mitochondrial impairments observed in autosomal dominant polycystic kidney disease. Methods: Using control and Pkd1-/- kidney epithelial cells, we investigated peroxisome abundance, biogenesis and morphology by immunoblotting, immunofluorescent and live cell imaging of peroxisome-related proteins and assayed peroxisomal specific β-oxidation. We further analyzed fatty acid composition by mass spectrometry in kidneys of Pkd1fl/fl; Ksp-Cre mice. We also evaluated peroxisome lipid metabolism in published metabolomics datasets of Pkd1 mutant cells and kidneys. Lastly, we investigated if the C-terminus or full-length polycystin-1 co-localize with peroxisome markers by imaging studies. Results: Peroxisome abundance, morphology and peroxisome-related protein expression in Pkd1-/- cells were normal, suggesting preserved peroxisome biogenesis. Peroxisomal β-oxidation was not impaired in Pkd1-/- cells, and there was no obvious accumulation of very long chain fatty acids in kidneys of mutant mice. Re-analysis of published datasets provide little evidence of peroxisomal abnormalities in independent sets of Pkd1 mutant cells and cystic kidneys, while providing further evidence of mitochondrial fatty acid oxidation defects. Imaging studies with either full length polycystin-1 or its C-terminus, a fragment previously shown to go to the mitochondria, showed minimal co-localization with peroxisome markers. Conclusions: Our studies showed that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid metabolism.

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Increased mitochondrial fragmentation in polycystic kidney disease acts as a modifier of disease progression

Cited by 40 publications

References 34 publications

The Role of Mitochondria in Acute Kidney Injury and Chronic Kidney Disease and Its Therapeutic Potential

The Role of Mitochondria in Acute Kidney Injury and Chronic Kidney Disease and Its Therapeutic Potential

Loss of Mitochondrial Control Impacts Renal Health

Pkd1mutation has no apparent effects on peroxisome structure or lipid metabolism

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