Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

Abstract

The endoplasmic reticulum (ER) stress and mitochondrial dysfunction in high glucose (HG)-induced podocyte injury have been demonstrated to the progression of diabetic kidney disease (DKD). However, the pathological mechanisms remain equivocal. Mitofusin2 (Mfn2) was initially identified as a dynamin-like protein involved in fusing the outer mitochondrial membrane (OMM). More recently, Mfn2 has been reported to be located at the ER membranes that contact OMM. Mitochondria-associated ER membranes (MAMs) is the intercellular membrane subdomain, which connects the mitochondria and ER through a proteinaceous tether. Here, we observed the suppression of Mfn2 expression in the glomeruli and glomerular podocytes of patients with DKD. Streptozotocin (STZ)-induced diabetic rats exhibited abnormal mitochondrial morphology and MAMs reduction in podocytes, accompanied by decreased expression of Mfn2 and activation of all three unfolded protein response (UPR) pathways (IRE1, ATF6, and PERK). The HG-induced mitochondrial dysfunction, MAMs reduction, and increased apoptosis in vitro were accompanied by the downregulation of Mfn2 and activation of the PERK pathway. Mfn2 physically interacts with PERK, and HG promotes a decrease in Mfn2-PERK interaction. In addition, Mfn2-silenced podocytes showed mitochondrial dysfunction, MAMs reduction, activation of PERK pathway, and increased apoptosis. Conversely, all these effects of HG stimulation were alleviated significantly by Mfn2 overexpression. Furthermore, the inhibition of PERK phosphorylation protected mitochondrial functions but did not affect the expression of Mfn2 in HG-treated podocytes. Therefore, this study confirmed that Mfn2 regulates the morphology and functions of MAMs and mitochondria, and exerts anti-apoptotic effects on podocytes by inhibiting the PERK pathway. Hence, the Mfn2-PERK signaling pathway may be a new therapeutic target for preventing podocyte injury in DKD.

Mitochondrial Dysfunction in Individuals with Diabetic Kidney Disease: A Systematic Review

“…The population characteristics varied across each study cohort, and a summary is provided in Table 1 . Of the 22 articles included in the systematic review, two articles included only individuals with T1DM [ 45 , 46 ], 10 articles included only individuals with T2DM [ 17 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ], three articles included both T1DM and T2DM [ 56 , 57 , 58 ], and seven articles did not specify [ 59 , 60 , 61 , 62 , 63 , 64 , 65 ]. Most studies included middle-to-older age subjects with a long duration (~15 years) of diabetes.…”

“…As mtDNA content and repair are largely influenced by mitochondrial dynamics, we profiled mitochondrial dynamics in individuals with DKD ( Table 3 ). Mitochondrial fission/fragmentation was reported in four studies [ 17 , 56 , 59 , 62 ], fusion in three studies [ 17 , 56 , 64 ], biogenesis in six studies [ 49 , 50 , 55 , 56 , 58 , 61 ], apoptosis in three studies [ 17 , 58 , 60 ], and one study reported on mitophagy [ 56 ].…”

Mitofusins: from mitochondria to fertility

“…Mfn2 plays a key role in Ca 2+ regulation by influencing the transport of Ca 2+ from the ER to the mitochondria [ 56 , 57 ]. Mfn2 also regulates the mitochondrial response to Ca 2+ and prevents cell fate from moving towards calcium-mediated apoptosis by converting the network morphology of the mitochondria [ 58 ]. In normal mitochondrial metabolism, Ca 2+ transport is a fundamental event for maintaining mitochondrial homeostasis.…”

Mitochondria-Endoplasmic Reticulum Contacts: The Promising Regulators in Diabetic Cardiomyopathy

“…Gao et al indicated that with the aggravation of oxidative stress injury in DM, the cardiac MFN2 mRNA level decreased [ 79 ]. A recent study revealed that in high glucose (HG)-induced podocytes, HG activated the PERK pathway by downregulating MFN2 expression and reducing MFN2-PERK interaction [ 80 ]. Therefore, we speculate that the downregulation of MFN2 in cardiomyocytes under high glucose environment may lead to dissociation and continuous activation of PERK, which subsequently initiates UPR and ER stress.…”