The complicated role of mitochondria in the podocyte - PubMed (original) (raw)
The complicated role of mitochondria in the podocyte
Nehaben A Gujarati et al. Am J Physiol Renal Physiol. 2020.
Abstract
Mitochondria play a complex role in maintaining cellular function including ATP generation, generation of biosynthetic precursors for macromolecules, maintenance of redox homeostasis, and metabolic waste management. Although the contribution of mitochondrial function in various kidney diseases has been studied, there are still avenues that need to be explored under healthy and diseased conditions. Mitochondrial damage and dysfunction have been implicated in experimental models of podocytopathy as well as in humans with glomerular diseases resulting from podocyte dysfunction. Specifically, in the podocyte, metabolism is largely driven by oxidative phosphorylation or glycolysis depending on the metabolic needs. These metabolic needs may change drastically in the presence of podocyte injury in glomerular diseases such as diabetic kidney disease or focal segmental glomerulosclerosis. Here, we review the role of mitochondria in the podocyte and the factors regulating its function at baseline and in a variety of podocytopathies to identify potential targets for therapy.
Keywords: glomerulosclerosis; kidney disease; mitochondria; podocytes; proteinuria.
Conflict of interest statement
No conflicts of interest, financial or otherwise, are declared by the authors.
Figures
Graphical abstract
Fig. 1.
Mitochondrial dynamics and respiratory complex. Mitochondrial biogenesis is mainly regulated by peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and mitochondrial fission and fusion are regulated by dynamin-related protein-1 (Drp1) and mitofusin-1 (Mfn1), mitofusin-2 (Mfn2), and optic atrophy 1 (Opa1) respectively. The damaged mitochondria result in excessive reactive oxygen species (ROS) generation that can be inhibited by mitochondrial enzymes such as superoxide dismutase 2 (SOD2). Damaged mitochondria with decreased mtDNA undergo mitophagy. The electron transport chain (ETC) in the inner mitochondrial membrane consists of five respiratory complexes (complexes I–V). The flow of electrons through these complexes along with proton gradient leads to the generation of ATP. A wide array of genes involved in mitochondrial homeostasis and ETC have been identified to play a critical role in maintaining podocyte health and function and therefore have been associated with various podocytopathies. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) has been reported to increase mitochondrial biogenesis through AMP-activated protein kinase (AMPK)-mediated phosphorylation of PGC-1α. Other regulators of PGC-1α, such as sirtuin 1 (SIRT1) and taurine-upregulated gene 1 (Tug1), have been also studied in podocytopathies. Drp1 phosphorylation by Rho-associated coiled coil-containing protein kinase 1 (ROCK1) and Ca2+/calmodulin-dependent kinase-1α (CaMK1α) promotes mitochondrial fission, whereas phosphorylation by cAMP and its activator, 8-(4-chlorophenylthio)adenosine cAMP (pCPT-cAMP), leads to inhibition of mitochondrial fission. Inhibition of respiratory complex II by rotenone has been found to attenuate diabetic kidney disease (DKD); transcriptional factor Krüppel-like factor 6 (KLF6) and its downstream target, mitochondrial cytochrome c oxidase assembly gene (SCO2), a complex IV assembly factor, have been reported to play a role in glomerulopathies.
References
- Abe Y, Sakairi T, Beeson C, Kopp JB. TGF-β1 stimulates mitochondrial oxidative phosphorylation and generation of reactive oxygen species in cultured mouse podocytes, mediated in part by the mTOR pathway. Am J Physiol Renal Physiol 305: F1477–F1490, 2013. doi: 10.1152/ajprenal.00182.2013. - DOI - PMC - PubMed
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