Hyperglycemia alters mitochondrial respiration efficiency and mitophagy in human podocytes

Audzeyenka, Irena; Rachubik, Patrycja; Typiak, Marlena; Kulesza, Tomasz; Topolewska, Anna; Rogacka, Dorota; Angielski, S; Saleem, Moin A.; Piwkowska, Agnieszka

doi:10.1016/j.yexcr.2021.112758

Cited by 34 publications

(31 citation statements)

References 62 publications

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“…A reduction in oxidative phosphorylation (OXPHOS) and ATP production has been demonstrated in DN in addition to podocyte “glycolytic switch.” (D) Mitochondrial dynamics. A reduction in podocyte mitochondrial biogenesis pathways are observed in DN alongside a reduction in mitochondrial fusion, an increase in podocyte mitochondrial fission ( 22 , 70 ) and a reduction in podocyte mitophagy ( 81 ). (E) Altered podocyte redox signaling in DN is evidenced by an increase in NADPH oxidases ( 32 ), an increase in reactive oxygen species ( 34 ), a reduction in sirtuins which can lead to a reduction in FOXO1 ( 62 ).…”

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confidence: 99%

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

2021

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Diabetic Nephropathy (DN) is the leading cause of kidney failure, with an increasing incidence worldwide. Mitochondrial dysfunction is known to occur in DN and has been implicated in the underlying pathogenesis of disease. These complex organelles have an array of important cellular functions and involvement in signalling pathways; and understanding the intricacies of these responses in health, as well as how they are damaged in disease, is likely to highlight novel therapeutic avenues. A key cell type damaged early in DN is the podocyte and increasing studies have focused on investigating the role of mitochondria in podocyte injury. This review will summarise what is known about podocyte mitochondrial dynamics in DN, with a particular focus on bioenergetic pathways, highlighting key studies in this field and potential opportunities to target, enhance or protect podocyte mitochondrial function in the treatment of DN.

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confidence: 99%

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

2021

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“…In agreement with this, similar findings were shown in corneal endothelial cells harvested from advanced diabetic human donors [ 38 ]. Likewise, outside the eye, work carried out in kidney cells and streptozotocin-treated rats has also found hyperglycemia-induced changes in mitochondrial bioenergetics and a decrease in spare respiratory capacity [ 40 , 43 ]. As the main energy reserve for a cell, spare respiratory capacity is an integral factor in the ability of a cell to respond to stress.…”

Section: Discussionmentioning

confidence: 99%

Chronic Hyperglycemia Compromises Mitochondrial Function in Corneal Epithelial Cells: Implications for the Diabetic Cornea

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et al. 2022

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Mitochondrial dysfunction is a major pathophysiological event leading to the onset of diabetic complications. This study investigated the temporal effects of hyperglycemia on mitochondrial metabolism in corneal epithelial cells. To accomplish this, human telomerase-immortalized corneal epithelial cells were cultured in a defined growth medium containing 6 mM glucose. To simulate hyperglycemia, cells were cultured in a medium containing 25 mM D-glucose, and control cells were cultured in mannitol. Using metabolic flux analysis, there was a hyperosmolar-mediated increase in mitochondrial respiration after 24 h. By day 5, there was a decrease in spare respiratory capacity in cells subject to high glucose that remained suppressed throughout the 14-day period. Although respiration remained high through day 9, glycolysis was decreased. Mitochondrial respiration was decreased by day 14. This was accompanied by the restoration of glycolysis to normoglycemic levels. These changes paralleled a decrease in mitochondrial polarization and cell cycle arrest. Together, these data show that chronic but not acute hyperglycemic stress leads to mitochondrial dysfunction. Moreover, the hyperglycemia-induced loss of spare respiratory capacity reduces the ability of corneal epithelial cells to respond to subsequent stress. Compromised mitochondrial function represents a previously unexplored mechanism that likely contributes to corneal complications in diabetes.

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“…mtDNA is highly susceptible to oxidative stress because of lack of protective histone proteins and proximity to mtROS and there is renal accumulation of oxidative mtDNA lesions and loss of mtDNA copy number in experimental DN [ 260 , 261 ]. High glucose, aldosterone, and peroxide hydrogen reduce mtDNA in podocytes [ 262 , 263 ] and mtDNA-depleted podocytes show increased mtROS levels, reduced mitochondrial membrane potential, and nephrin down-regulation [ 262 ]. Mechanisms of mtDNA repair are highly relevant and podocyte-specific deletion of Mpv17, which is involved in mtDNA maintenance, results in mitochondrial dysfunction and severe glomerular disease under conditions of stress [ 264 ].…”

Section: Mechanisms Of Podocyte Injurymentioning

confidence: 99%

Mechanisms of podocyte injury and implications for diabetic nephropathy

2022

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Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, and diabetic nephropathy (DN). Moreover, albuminuria is an important feature of all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining the permselectivity of the glomerular filtration barrier (GFB) and injury of the podocyte, leading to foot process (FP) effacement and podocyte loss, the unifying underlying mechanism of proteinuric glomerulopathies. The metabolic insult of hyperglycemia is of paramount importance in the pathogenesis of DN, while insults leading to podocyte damage are poorly defined in other proteinuric glomerulopathies. However, shared mechanisms of podocyte damage have been identified. Herein, we will review the role of haemodynamic and oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, and both mitochondrial and autophagic dysfunction in the pathogenesis of the podocyte damage, focussing particularly on their role in the pathogenesis of DN. Gaining a better insight into the mechanisms of podocyte injury may provide novel targets for treatment. Moreover, novel strategies for boosting podocyte repair may open the way to podocyte regenerative medicine.

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Hyperglycemia alters mitochondrial respiration efficiency and mitophagy in human podocytes

Cited by 34 publications

References 62 publications

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

Chronic Hyperglycemia Compromises Mitochondrial Function in Corneal Epithelial Cells: Implications for the Diabetic Cornea

Mechanisms of podocyte injury and implications for diabetic nephropathy

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