Endoplasmic reticulum mitochondria contacts modulate apoptosis of renal cells and its implications in diabetic neuropathy

In diabetic neuropathy (DN), the kidney injury occurs as the renal as a keymitochondrial fusion protein implicated in MAM of POMC neucells undergo apoptotic-mediate d cell death [1]. Current therapeutics can barely reverse course of the disease progression, and this necessitates the better understanding of mechanisms underlying disease pathogenesis in order to design effective strategies. Cells induce apoptosis in scenarios such as endoplasmic reticulum (ER) stress and presence of irreparably damaged mitochondria [2]. Recently emerging concept that ER and mitochondria communicate at a specific interface called MAM (mitochondria associated ER membranes) is important for cellular as well as organismal homeostasis [3]. Although the evidences suggesting existence of membrane contact sites can be traced back to 1980's literature, the field was really re-born after a seminal study published in 2009, that deciphered the tethering factors at MAM [3]. MAM is vital for carrying out various essential cellular pathways such as autophagy, lipid synthesis, calcium exchange and mitochondrial DNA replication [4–6]. MAM interface spans around 10 nm area of the juxtaposed ER and mitochondrial membranes. This interface not only helps in attaining and maintaining homeostasis but also altering the signaling events during stress conditions [3]. Perturbation in MAM integrity elevates oxidative stress, compromises autophagy aswell as reducesmitochondrial respiration [6]. As shown by Marc claret and colleagues, in diet-induced obesity mice, the mitofusin-mediated altercations (MAM defect) in proopiomelanocortin (POMC) neurons affect POMC processing, increases ER stress and leptin resistance [7]. This previous study documented the role ofmalfunctioningMAM in POMCneurons towards regulating the pathology of diet-induced obesity. However, the role of MAM dysfunction in driving the apoptotic death of renal cells has not been explored yet. The article by Yang et al., in EBioMedicine demonstrated the clinically relevant and previously undocumented role of Disulfide-bond A oxidoreductase-like protein (DsbA-L) in regulatingMAM that alter apoptotic signaling events of renal cells during progression of diabetes [8]. DsbA-L is a cellular detoxifying enzyme that is involved in catalyzing the formation of disulphide bonds during adiponectin multimerization in adipocytes [9]. Previous studies have showed a protective role for DsbA-L against diet-induced obesity and insulin resistance [10]. Earlier studies have highlighted a role of dysregulated mitofusin-2 (MFN-2)