Analysis of Brain, Blood, and Testis Phenotypes Lacking the Vps13a Gene in C57BL/6N Mice.

The Vps13a gene encodes a lipid transfer protein called VPS13A, or chorein, associated with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondria-endosomes, and lipid droplets. This protein plays a crucial role in inter-organelle communication and lipid transport. Mutations in the VPS13A gene are implicated in the pathogenesis of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder characterized by chorea, orofacial dyskinesias, hyperkinetic movements, seizures, cognitive impairment, and acanthocytosis. Previous mouse models of ChAc have shown variable disease phenotypes depending on the genetic background. In this study, we report the generation of a Vps13a flox allele in a pure C57BL/6N mouse background and the subsequent creation of Vps13a knockout (KO) mice via Cre-recombination. Our Vps13a KO mice exhibited increased reticulocytes but not acanthocytes in peripheral blood smears. Additionally, there were no significant differences in the GFAP- and Iba1-positive cells in the striatum, the basal ganglia of the central nervous system. Interestingly, we observed abnormal spermatogenesis leading to male infertility. These findings indicate that Vps13a KO mice are valuable models for studying male infertility and some hematological aspects of ChAc.

IP3R2 regulates apoptosis by Ca2+ transfer through mitochondria-ER contacts in hypoxic photoreceptor injury.

Mitochondria-associated ER membranes (MAMs) are contact sites that enable bidirectional communication between the ER (endoplasmic reticulum) and mitochondria, including the transfer of Ca2+ signals. MAMs are essential for mitochondrial function and cellular energy metabolism. However, unrestrained Ca2+ transfer to the mitochondria can lead to mitochondria-dependent apoptosis. IP3R2 (Inositol 1,4,5-trisphosphate receptor 2) is an important intracellular Ca2+ channel. This study investigated the contribution of IP3R2-MAMs to hypoxia-induced apoptosis in photoreceptor cells. A photoreceptor hypoxia model was established by subretinal injection of hyaluronic acid (1%) in C57BL/6 mice and 1% O2 treatment in 661W cells. Transmission electron microscopy (TEM), ER-mitochondria colocalization, and the MAM reporter were utilized to evaluate MAM alterations. Cell apoptosis and mitochondrial homeostasis were evaluated using immunofluorescence (IF), flow cytometry, western blotting (WB), and ATP assays. SiRNA transfection was employed to silence IP3R2 in 661W cells. Upon hypoxia induction, MAMs were significantly increased in photoreceptors both in vivo and in vitro. This was accompanied by the activation of mitochondrial apoptosis and disruption of mitochondrial homeostasis. Elevated MAM-enriched IP3R2 protein levels induced by hypoxic injury led to mitochondrial calcium overload and subsequent photoreceptor apoptosis. Notably, IP3R2 knockdown not only improved mitochondrial morphology but also restored mitochondrial function in photoreceptors by limiting MAM formation and thereby attenuating mitochondrial calcium overload under hypoxia. Our results suggest that IP3R2-MAM-mediated mitochondrial calcium overload plays a critical role in mitochondrial dyshomeostasis, ultimately contributing to photoreceptor cell death. Targeting MAM constitutive proteins might provide an option for a therapeutic approach to mitigate photoreceptor death in retinal detachment.

Dialogue between mitochondria and endoplasmic reticulum-potential therapeutic targets for age-related cardiovascular diseases.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) act as physical membrane contact sites facilitating material exchange and signal transmission between mitochondria and endoplasmic reticulum (ER), thereby regulating processes such as Ca2+/lipid transport, mitochondrial dynamics, autophagy, ER stress, inflammation, and apoptosis, among other pathological mechanisms. Emerging evidence underscores the pivotal role of MAMs in cardiovascular diseases (CVDs), particularly in aging-related pathologies. Aging significantly influences the structure and function of the heart and the arterial system, possibly due to the accumulation of reactive oxygen species (ROS) resulting from reduced antioxidant capacity and the age-related decline in organelle function, including mitochondria. Therefore, this paper begins by describing the composition, structure, and function of MAMs, followed by an exploration of the degenerative changes in MAMs and the cardiovascular system during aging. Subsequently, it discusses the regulatory pathways and approaches targeting MAMs in aging-related CVDs, to provide novel treatment strategies for managing CVDs in aging populations.

Mitochondria-associated endoplasmic reticulum membranes involve in oxidative stress-induced intestinal barrier injury and mitochondrial dysfunction under diquat exposing.

Many factors induced by environmental toxicants have made oxidative stress a risk factor for the intestinal barrier injury and growth restriction, which is serious health threat for human and livestock and induces significant economic loss. It is well-known that diquat-induced oxidative stress is implicated in the intestinal barrier injury. Although some studies have shown that mitochondria are the primary target organelle of diquat, the underlying mechanism remains incompletely understood. Recently, mitochondria-associated endoplasmic reticulum membranes (MAMs) have aroused increasing concerns among scholars, which participate in mitochondrial dynamics and signal transduction. In this study, we investigated whether MAMs involved in intestinal barrier injury and mitochondrial dysfunction induced by diquat-induced oxidative stress in piglets and porcine intestinal epithelial cells (IPEC-J2 cells). The results showed that diquat induced growth restriction and impaired intestinal barrier. The mitochondrial reactive oxygen species (ROS) was increased and mitochondrial membrane potential was decreased following diquat exposure. The ultrastructure of mitochondria and MAMs was also disturbed. Meanwhile, diquat upregulated endoplasmic reticulum stress marker protein and activated PERK pathway. Furthermore, loosening MAMs alleviated intestinal barrier injury, decrease of antioxidant enzyme activity and mitochondrial dysfunction induced by diquat in IPEC-J2 cells, while tightening MAMs exacerbated diquat-induced mitochondrial dysfunction. These results suggested that MAMs may be associated with the intestinal barrier injury and mitochondrial dysfunction induced by diquat in the jejunum of piglets.

Dietary α-Ketoglutarate Alleviates Escherichia coli LPS-Induced Intestinal Barrier Injury by Modulating the Endoplasmic Reticulum-Mitochondrial System Pathway in Piglets.

BACKGROUND: α-Ketoglutarate (AKG) plays a pivotal role in mitigating inflammation and enhancing intestinal health. OBJECTIVES: This study aimed to investigate whether AKG could protect against lipopolysaccharide (LPS)-induced intestinal injury by alleviating disorders in mitochondria-associated endoplasmic reticulum (MAM) membranes, dysfunctional mitochondrial dynamics, and endoplasmic reticulum (ER) stress in a piglet model. METHODS: Twenty-four piglets were subjected to a 2 × 2 factorial design with dietary factors (basal diet or 1% AKG diet) and LPS treatment (LPS or saline). After 21 d of consuming either the basal diet or AKG diet, piglets received injections of LPS or saline. The experiment was divided into 4 treatment groups [control (CON) group: basal diet + saline; LPS group: basal diet +LPS; AKG group: AKG diet + saline; and AKG_LPS group: AKG + LPS], each consisting of 6 piglets. RESULTS: The results demonstrated that compared with the CON group, AKG enhanced jejunal morphology, antioxidant capacity, and the messenger RNA and protein expression of tight junction proteins. Moreover, it has shown a reduction in serum diamine oxidase activity and D-lactic acid content in piglets. In addition, fewer disorders in the ER-mitochondrial system were reflected by AKG, as evidenced by AKG regulating the expression of key molecules of mitochondrial dynamics (mitochondrial calcium uniporter, optic atrophy 1, fission 1, and dynamin-related protein 1), ER stress [activating transcription factor (ATF) 4, ATF 6, CCAAT/enhancer binding protein homologous protein, eukaryotic initiation factor 2α, glucose-regulated protein (GRP) 78, and protein kinase R-like ER kinase], and MAM membranes [mitofusin (Mfn)-1, Mfn-2, GRP 75, and voltage-dependent anion channel-1]. CONCLUSIONS: Dietary AKG can prevent mitochondrial dynamic dysfunction, ER stress, and MAM membrane disorder, ultimately alleviating LPS-induced intestinal damage in piglets.

Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic Reticulum-Mitochondria Interaction.

Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER-mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood-brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER-mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.

Deoxynivalenol induced intestinal barrier injury, mitochondrial dysfunction and calcium overload by inositol 1,4,5-triphosphate receptors (IP3Rs)-mitochondrial calcium uniporter (MCU) calcium axis.

Deoxynivalenol (DON) contamination is widespread in crops and could easily cause intestinal injury, which brings hazards to animals. Mitochondria are considered as an important target of DON, nevertheless, the mechanism is still unclear. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) have gained arousing interest and are recognized as critical signaling hubs that control calcium signaling transduction between ER and mitochondria. This study aims to investigate the effects of DON on intestinal barrier, mitochondria, MAMs and inositol 1,4,5-triphosphate receptors (IP3Rs)-mitochondrial calcium uniporter (MCU) calcium axis in piglets and porcine intestinal epithelial cells (IPEC-J2). Furthermore, inhibition of IP3Rs or MCU was used to explore whether IP3Rs-MCU axis of MAMs was involved in the mitochondria dysfunction and intestinal epithelium barrier injury induced by DON in IPEC-J2. The data showed that DON induced intestinal barrier injury, mitochondrial dysfunction and ERS in piglets' jejunum and IPEC-J2. Moreover, DON increased MAMs by upregulating the protein level of Mitofusin 2 (Mfn2), increasing the percentage of mitochondria with MAMs/total mitochondria and the ratio of MAMs length/mitochondrial perimeter and shortening the distance between mitochondria and ER of MAMs. Importantly, DON influenced IP3Rs-glucose-regulated protein 75 (GRP75)-voltage-dependent anion channel 1 (VDAC1)-MCU calcium axis by increasing the protein levels of GRP75 and MCU and the interaction of VDAC1-GRP75-IP3Rs complex, which in turn induced mitochondrial calcium overload. Furthermore, inhibition of IP3Rs or MCU alleviated DON-induced intestinal epithelium barrier injury, mitochondrial dysfunction and mitochondrial calcium overload of IPEC-J2. The current investigation proposed that DON induced intestinal injury, mitochondrial dysfunction and calcium overload via IP3Rs-GRP75-VDAC1-MCU calcium axis.

Mfn2 regulates mitochondria-associated ER membranes to affect PCOS oocyte development.

This study aimed to investigate the role of mitochondrial-related protein Mfn2 in polycystic ovary syndrome (PCOS) and its impact on oocyte development. The pathological features of PCOS model mice were confirmed by hematoxylin-eosin staining and immunohistochemistry. The expression of Mfn2 and mitochondrial-related proteins in PCOS oocytes and granulosa cells was detected by qRT-PCR and Western blot. Mitochondrial quantity was measured by Mito-Tracker staining, and the structure of mitochondria-associated ER membranes (MAMs) was observed by transmission electron microscopy. The results showed that Mfn2 was significantly downregulated in PCOS oocytes and granulosa cells, and its expression was inhibited in oocytes at different developmental stages. Moreover, the structure of MAMs was also disrupted. Downregulation of Mfn2 expression led to a reduction in mitochondrial quantity in oocytes and granulosa cells, as well as disruption of MAM structure, while overexpression of Mfn2 had the opposite effect. In conclusion, this study indicates that Mfn2 affects the development of PCOS oocytes by regulating MAMs and may be involved in maintaining the stability of MAM structure and function, thereby affecting mitochondrial quantity and function. These findings provide new insights into the pathogenesis and treatment of PCOS.

Down-regulation of the mitochondrial fusion protein Opa1/Mfn2 promotes cardiomyocyte hypertrophy in Su5416/hypoxia-induced pulmonary hypertension rats.

BACKGROUND: Maladaptive right ventricular (RV) remodeling is the most important pathological feature of pulmonary hypertension (PH), involving processes such as myocardial hypertrophy and fibrosis. A growing number of studies have shown that mitochondria-associated endoplasmic reticulum membranes (MAMs) are involved in various physiological and pathological processes, such as calcium homeostasis, lipid metabolism, inflammatory response, mitochondrial dynamics, and autophagy/mitophagy. The abnormal expression of MAMs-related factors is closely related to the occurrence and development of heart-related diseases. However, the role of MAM-related factors in the maladaptive RV remodeling of PH rats remains unclear. METHODS AND RESULTS: We first obtained the transcriptome data of RV tissues from PH rats induced by Su5416 combined with hypoxia treatment (SuHx) from the Gene Expression Omnibus (GEO) database. The results showed that two MAMs-related genes (Opa1 and Mfn2) were significantly down-regulated in RV tissues of SuHx rats, accompanied by significant up-regulation of cardiac hypertrophy-related genes (such as Nppb and Myh7). Subsequently, using the SuHx-induced PH rat model, we found that the downregulation of mitochondrial fusion proteins Opa1 and Mfn2 may be involved in maladaptive RV remodeling by accelerating mitochondrial dysfunction. Finally, at the cellular level, we found that overexpression of Opa1 and Mfn2 could inhibit hypoxia-induced mitochondrial fission and reduce ROS production in H9c2 cardiomyocytes, thereby retarded the progression of cardiomyocyte hypertrophy. CONCLUSIONS: The down-regulation of mitochondrial fusion protein Opa1/Mfn2 can accelerate cardiomyocyte hypertrophy and then participate in maladaptive RV remodeling in SuHx-induced PH rats, which may be potential targets for preventing maladaptive RV remodeling.

Zearalenone induces mitochondria-associated endoplasmic reticulum membranes dysfunction in piglet Sertoli cells based on endoplasmic reticulum stress.

Zearalenone (ZEA) is an estrogen-like mycotoxin, which mainly led to reproductive toxicity. The study aimed to investigate the molecular mechanism of ZEA-induced dysfunction of mitochondria-associated endoplasmic reticulum membranes (MAM) in piglet Sertoli cells (SCs) via the endoplasmic reticulum stress (ERS) pathway. In this study, SCs were used as a research object that was exposed to ZEA, and ERS inhibitor 4-Phenylbutyrate acid (4-PBA) was used as a reference. The results showed that ZEA damaged cell viability and increased Ca2+ levels; damaged the structure of MAM; up-regulated the relative mRNA and protein expression of glucose-regulated protein 75 (Grp75) and mitochondrial Rho-GTPase 1 (Miro1), while inositol 1,4,5-trisphosphate receptor (IP3R), voltage-dependent anion channel 1 (VDAC1), mitofusin2 (Mfn2) and phosphofurin acidic cluster protein 2 (PACS2) were down-regulated. After a 3 h 4-PBA-pretreatment, ZEA was added for mixed culture. The results of 4-PBA pretreatment showed that inhibition of ERS reduced the cytotoxicity of ZEA against piglet SCs. Compared with the ZEA group, inhibition of ERS increased cell viability and decreased Ca2+ levels; restored the structural damage of MAM; down-regulated the relative mRNA and protein expression of Grp75 and Miro1; and up-regulated the relative mRNA and protein expression of IP3R, VDAC1, Mfn2, and PACS2. In conclusion, ZEA can induce MAM dysfunction in piglet SCs via the ERS pathway, whereas ER can regulate mitochondria through MAM.

Mitochondria-associated endoplasmic reticulum membranes: A promising toxicity regulation target.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic suborganelle membranes that physically couple endoplasmic reticulum (ER) and mitochondria to provide a platform for exchange of intracellular molecules and crosstalk between the two organelles. Dysfunctions of mitochondria and ER and imbalance of intracellular homeostasis have been discovered in the research of toxics. Cellular activities such as oxidative stress, ER stress, Ca2+ transport, autophagy, mitochondrial fusion and fission, and apoptosis mediated by MAMs are closely related to the toxicological effects of various toxicants. These cellular activities mediated by MAMs crosstalk with each other. Regulating the structure and function of MAMs can alleviate the damage caused by toxicants to some extent. In this review, we discuss the relationships between MAMs and the mechanisms of toxicological effects, and highlight MAMs as a potential target for protection against toxicants.

Recent advances of DJ-1 regulating mitochondrial function / 中国药理学通报

Dj-l is a protein encoded by PARK7 gene, a member of the peptidase C56 protein family. Defects in PARK7 gene may lead to autosomal recessive early-onset Parkinson ' s disease. Dj-1 is a multifunctional protein that acts as an active androgen receptor-mediated transcriptional regulator, a REDOX sensitive molecular chaperone, an oxidative stress sensor, and it also protects neurons from oxidative stress and cell death. In addition, DJ-1 is also associated with mitochondria, energy metabolism, mitochondrial homeostasis, mitophagy mitochondria-associated endoplasmic reticulum membranes and other life processes. However, the precise function of DJ-1 protein is not well understood. This paper reviews the effect, mechanism and molecular basis of DJ-1 protein in regulating mitochondrial function, and discusses its potential value in combination with clinical diseases. It has good timeliness, necessity, innovation and science, and also helps to provide new targets and ideas for clinical drug development.

The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury.

Earlier studies from our lab identified endoplasmic reticulum (ER) chaperone BiP/GRP78, an important component of MAM, to be a novel determinant of endothelial cell (EC) dysfunction associated with acute lung injury (ALI). Sigma1R (Sig1R) is another unique ER receptor chaperone that has been identified to associate with BiP/GRP78 at the MAM and is known to be a pluripotent modulator of cellular homeostasis. However, it is unclear if Sig1R also plays a role in regulating the EC inflammation and permeability associated with ALI. Our data using human pulmonary artery endothelial cells (HPAECs) showed that siRNA-mediated knockdown of Sig1R potentiated LPS-induced the expression of proinflammatory molecules ICAM-1, VCAM-1 and IL-8. Consistent with this, Sig1R agonist, PRE-084, known to activate Sig1R by inducing its dissociation from BiP/GRP78, blunted the above response. Notably, PRE-084 failed to blunt LPS-induced inflammatory responses in Sig1R-depleted cells, confirming that the effect of PRE-084 is driven by Sig1R. Furthermore, Sig1R antagonist, NE-100, known to inactivate Sig1R by blocking its dissociation from BiP/GRP78, failed to block LPS-induced inflammatory responses, establishing that dissociation from BiP/GRP78 is required for Sig1R to exert its anti-inflammatory action. Unlike Sig1R, the siRNA-mediated knockdown or Subtilase AB-mediated inactivation of BiP/GRP78 protected against LPS-induced EC inflammation. Interestingly, the protective effect of BiP/GRP78 knockdown or inactivation was abolished in cells that were depleted of Sig1R, confirming that BiP/GRP78 knockdown/inactivation-mediated suppression of EC inflammation is mediated via Sig1R. In view of these findings, we determined the in vivo relevance of Sig1R in a mouse model of sepsis-induced ALI. The intraperitoneal injection of PRE-084 mitigated sepsis-induced ALI, as evidenced by a decrease in ICAM-1, IL-6 levels, lung PMN infiltration, and lung vascular leakage. Together, these data evidence a protective role of Sig1R against endothelial dysfunction associated with ALI and identify it as a viable target in terms of controlling ALI in sepsis.

Compositions and Functions of Mitochondria-Associated Endoplasmic Reticulum Membranes and Their Contribution to Cardioprotection by Exercise Preconditioning.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are important components of intracellular signaling and contribute to the regulation of intracellular Ca2+/lipid homeostasis, mitochondrial dynamics, autophagy/mitophagy, apoptosis, and inflammation. Multiple studies have shown that proteins located on MAMs mediate cardioprotection. Exercise preconditioning (EP) has been shown to protect the myocardium from adverse stimuli, but these mechanisms are still being explored. Recently, a growing body of evidence points to MAMs, suggesting that exercise or EP may be involved in cardioprotection by modulating proteins on MAMs and subsequently affecting MAMs. In this review, we summarize the latest findings on MAMs, analyzing the structure and function of MAMs and the role of MAM-related proteins in cardioprotection. We focused on the possible mechanisms by which exercise or EP can modulate the involvement of MAMs in cardioprotection. We found that EP may affect MAMs by regulating changes in MFN2, MFN1, AMPK, FUNDC1, BECN1, VDAC1, GRP75, IP3R, CYPD, GSK3ß, AKT, NLRP3, GRP78, and LC3, thus playing a cardioprotective role. We also provided direction for future studies that may be of interest so that more in-depth studies can be conducted to elucidate the relationship between EP and cardioprotection.

Capsaicin Ameliorates the Loosening of Mitochondria-Associated Endoplasmic Reticulum Membranes and Improves Cognitive Function in Rats With Chronic Cerebral Hypoperfusion.

Based on accumulating evidence, vascular factors contribute to cognitive decline and dementia. Mitochondrial dysfunction is the core pathophysiological mechanism. Mitochondria-associated endoplasmic reticulum membranes (MAMs) are subcellular structures that physically and biologically connect mitochondria with the endoplasmic reticulum (ER) and regulate multiple functions ranging from calcium transfer to mitochondrial dynamics and bioenergetics. MAMs dysfunction has been speculated to be a key factor contributing to the pathogenesis of cognitive disorders and a new therapeutic target. However, the alteration of MAMs in vascular cognitive impairment remains to be revealed. Capsaicin, a specific agonist known to activated the transient receptor potential vanilloid type 1 (TRPV1), is involved in hippocampal synaptic plasticity and memory, but the detailed mechanism is still unclear. In this study, chronic cerebral hypoperfusion (CCH) model rats were created by bilateral common carotid artery occlusion (BCCAO), which is a widely used model to study vascular dementia. We observed that CCH rats showed obvious cognitive deficits, and ER-mitochondria contacts were loosener with lower expression of mitofusin2 (MFN2), a key protein connecting MAMs, in the hippocampal CA1 region, compared to the sham group. After capsaicin treatment for 12 weeks, we found that cognitive deficits induced by CCH were significantly alleviated and loosened ER-mitochondrial interactions were obviously improved. In conclusion, the findings of this study highlight that MAMs may contribute to the pathogenesis of cognitive impairment induced by CCH, and our new evidence that capsaicin improves cognitive function highlights a novel opportunity for drug discovery.

Potential role of mitochondria-associated endoplasmic reticulum membrane proteins in diseases.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic membrane coupling regions formed by the coupling of the mitochondrial outer membrane and endoplasmic reticulum (ER). MAMs are involved in the mitochondrial dynamics, mitophagy, Ca2+ exchange, and ER stress. A large number of studies indicate that many proteins are involved in the formation of MAMs, including dynamic-related protein 1 (Drp1), DJ-1, PTEN-induced putative kinase 1 (PINK), α-synuclein (α-syn), sigma-1 receptor (S1R), mitofusin-2 (Mfn2), presenilin-1 (PS1), protein kinase R (PKR)-like ER kinase (PERK), Parkin, Cyclophilin D (CypD), glucose-related protein 75 (Grp75), FUN14 domain containing 1 (Fundc1), vesicle-associated membrane-protein-associated protein B (VAPB), phosphofurin acidic cluster sorting protein 2 (PACS-2), ER oxidoreductin 1 (Ero1), and receptor expression-enhancing protein 1 (REEP1). These proteins play an important role in the structure and functions of the MAMs. Abnormalities in these MAM proteins further contribute to the occurrence and development of related diseases, such as neurodegenerative diseases, non-alcoholicfattyliverdisease (NALFD), type 2 diabetes mellitus (T2DM), and diabetic kidney (DN). In this review, we introduce important proteins involved in the structure and the functions of the MAMs. Furthermore, we effectively summarize major insights about these proteins that are involved in the physiopathology of several diseases through the effect on MAMs.

Mitochondrial redox-driven mitofusin 2 S-glutathionylation promotes neuronal necroptosis via disrupting ER-mitochondria crosstalk in cadmium-induced neurotoxicity.

Reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and mitochondrial dysfunction are known to affect the structural and functional damage in the neural system. Cadmium (Cd) is an environmental contaminant that is widely found in numerous environmental matrices and exhibits potential neurotoxic risk. However, it remains unclear how mitochondrial redox status induces, and whether Cd destabilizes, the ER-mitochondria crosstalk to have a toxic effect on the nervous system. Herein, in our present study, bioinformatics analysis revealed an important role of protein interaction and mitochondrial machinery in brain samples from Alzheimer's disease (AD) patients. Furthermore, we established a neurotoxicity model in vivo and in vitro induced by cadmium chloride (CdCl2). We demonstrated that CdCl2 exposure disrupts the balance in mitochondrial redox represented by enhanced mitochondrial ROS (mitoROS) levels, which enhance mitofusin 2 (Mfn2) S-glutathionylation and interrupt the mitochondria-associated ER membranes (MAMs) for crosstalk between the ER and mitochondria to induce neuronal necroptosis. Mechanistically, it was shown that CdCl2 exposure significantly enhances the mitochondria-associated degradation (MAD) of Mfn2 via S-glutathionylation, which inhibits Mfn2 localization to the MAMs and subsequently leads to the formation of the RIPK1-RIPK3-p-MLKL complex (a key component of the necrosome) at MAMs, to promote neuronal necroptosis. Furthermore, the glutaredoxin 1 (Grx1) catalyzed and Mfn2 overexpression restored S-glu-Mfn2, MAMs perturbation, necrosome formation, and necroptosis in neurons induced by CdCl2 exposure in vitro. Moreover, the intervention with antioxidants to reduce mitochondrial redox, such as N-acetyl-l-cysteine (NAC) and mitochondria-targeted antioxidant Mito-TEMPO, reduced the S-glutathionylation of Mfn2 involved in the antagonism of CdCl2-induced necroptosis and neurotoxicity in vivo and in vitro. Taken together, our results are the first time to demonstrate that S-glutathionylation of Mfn2 promotes neuronal necroptosis via disruption of ER-mitochondria crosstalk in CdCl2-induced neurotoxicity, providing the novel mechanistic insight into how hazardous chemical-induced adverse effects in various organs and tissues could be interpreted by intraorganellar pathways under the control of MAMs components in neurons.

Mitochondria-Associated Endoplasmic Reticulum Membranes in the Pathogenesis of Type 2 Diabetes Mellitus.

The endoplasmic reticulum (ER) and mitochondria are essential intracellular organelles that actively communicate via temporally and spatially formed contacts called mitochondria-associated membranes (MAMs). These mitochondria-ER contacts are not only necessary for the physiological function of the organelles and their coordination with each other, but they also control the intracellular lipid exchange, calcium signaling, cell survival, and homeostasis in cellular metabolism. Growing evidence strongly supports the role of the mitochondria-ER connection in the insulin resistance of peripheral tissues, pancreatic ß cell dysfunction, and the consequent development of type 2 diabetes mellitus (T2DM). In this review, we summarize current advances in the understanding of the mitochondria-ER connection and specifically focus on addressing a new perspective of the alterations in mitochondria-ER communication in insulin signaling and ß cell maintenance.

Mitochondria-Associated ER Membranes - The Origin Site of Autophagy.

Autophagy is a process of intracellular self-recycling and degradation that plays an important role in maintaining cell homeostasis. However, the molecular mechanism of autophagy remains to be further studied. Mitochondria-associated endoplasmic reticulum membranes (MAMs) are the region of the ER that mediate communication between the ER and mitochondria. MAMs have been demonstrated to be involved in autophagy, Ca2+ transport and lipid metabolism. Here, we discuss the composition and function of MAMs, more specifically, to emphasize the role of MAMs in regulating autophagy. Finally, some key information that may be useful for future research is summarized.