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.