Oxalate-induced damage to renal tubular epithelial cells (RTECs) is an essential factor in the incident kidney stone, but the specific mechanism is unclear. Recent research has pinpointed interacting areas within the endoplasmic reticulum and mitochondria, called mitochondria-associated membranes (MAMs). These studies have linked endoplasmic reticulum stress (ERS) and oxidative imbalance to kidney disease development. The sigma-1 receptor (S1R), a specific protein found in MAMs, is involved in various physiological processes, but its role in oxalate-induced kidney stone formation remains unclear. In this study, we established cellular and rat models of oxalate-induced kidney stone formation to elucidate the S1R\'s effects against ERS and apoptosis and its mechanism in oxalate-induced RTEC injury. We found that oxalate downregulated S1R expression in RTECs and escalated oxidative stress and ERS, culminating in increased apoptosis. The S1R agonist dimemorfan up-regulated S1R expression and mitigated ERS and oxidative stress, thereby reducing apoptosis. This protective effect was mediated through S1R inhibition of the CHOP pathway. Animal experiments demonstrated that S1R\'s activation attenuated oxalate-induced kidney injury and alleviated kidney stone formation. This is the first study to establish the connection between S1R and kidney stones, suggesting S1R\'s protective role in inhibiting ERS-mediated apoptosis to ameliorate kidney stone formation.

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by abnormal hepatic steatosis and inflammation. Previous studies have shown that Patchouli alcohol (PA), the primary component of Pogostemonis Herba, can alleviate digestive system diseases. However, its protection against MASH remains unclear. This study explored the protective effects and underlying mechanism of PA against high-fat diet-induced MASH in rats. Results showed that PA considerably reduced body weight, epididymal fat, and liver index and attenuated liver histological injury in MASH rats. PA alleviated hepatic injury by inhibiting steatosis and inflammation. These effects are associated with the improvement of SREBP-1c- and PPARα-mediated lipid metabolism and inhibition of the STING-signaling pathway-mediated inflammatory response. Moreover, PA-inhibited hepatic endoplasmic reticulum (ER) stress and mitochondrial dysfunction, reducing SREBP-1c and STING expressions and enhance PPARα expression. PA treatment had the strongest effect on the regulation of mitogen fusion protein 2 (Mfn2) in inhibiting mitochondrial dysfunction. Mfn2 is an important structural protein for binding ERs and mitochondria to form mitochondria-associated ER membranes (MAMs). MASH-mediated disruption of MAMs was inhibited after PA treatment-induced Mfn2 activation. Therefore, the pharmacological effect of PA on MASH is mainly attributed to the inhibition of MAM disruption-induced hepatic steatosis and inflammation. The findings of this study may have implications for MASH treatment that do not neglect the role of Mfn2-mediated MAMs.

Autophagy dysregulation and Ca 2+-induced mitochondrial dysfunction in trophoblast cells are proposed to contribute to preeclampsia (PE) development. FAM134B is identified as a receptor associated with endoplasmic reticulum autophagy (ER-phagy). In this study, the placentas of normal pregnant women and PE patients are collected and analyzed by immunohistochemistry, quantitative real-time PCR, and western blot analysis. The effects of ER-phagy are investigated in HTR8/SVneo cells. Significantly increased levels of FAM134B, inositol-1,4,5-triphosphate receptor type 1 (IP3R), calnexin, cleaved caspase 3 and cytochrome C are detected in the PE placenta and sodium nitroprusside (SNP)-treated HTR-8/SVneo cells. Overexpression of FAM134B in HTR-8/SVneo cells results in increased apoptosis, impaired invasion capacity, and diminished mitochondrial function, while an autophagy inhibitor improves mitochondrial performance. Excessive ER-phagy is also associated with an increased concentration of gamma linolenic acid. Our findings suggest that FAM134B contributes to trophoblast apoptosis by mediating ER-mitochondria Ca 2+ transfer through mitochondria-associated endoplasmic reticulum membranes (MAMs) and subsequent mitochondrial function, further enhancing our understanding of PE etiology.

Cardiovascular diseases (CVDs) are currently the leading cause of death worldwide. In 2022, the CVDs contributed to 19.8 million deaths globally, accounting for one-third of all global deaths. With an aging population and changing lifestyles, CVDs pose a major threat to human health. Mitochondria-associated endoplasmic reticulum membranes (MAMs) are communication platforms between cellular organelles and regulate cellular physiological functions, including apoptosis, autophagy, and programmed necrosis. Further research has shown that MAMs play a critical role in the pathogenesis of CVDs, including myocardial ischemia and reperfusion injury, heart failure, pulmonary hypertension, and coronary atherosclerosis. This suggests that MAMs could be an important therapeutic target for managing CVDs. The goal of this study is to summarize the protein complex of MAMs, discuss its role in the pathological mechanisms of CVDs in terms of its functions such as Ca2+ transport, apoptotic signaling, and lipid metabolism, and suggest the possibility of MAMs as a potential therapeutic approach.

Dominant variants in WFS1 (wolframin ER transmembrane glycoprotein), the gene coding for a mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein, have been associated with Wolfram-like syndrome (WLS). In vitro and in vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca2+) transfer, mitochondrial dysfunction, and enhanced macroautophagy/autophagy and mitophagy. However, in the WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that in human fibroblasts and murine neuronal cultures the WLS protein WFS1E864K leads to decreases in mitochondria bioenergetics and Ca2+ uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in the Wfs1E864K mouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM\'s integrity and functionality. It may open new treatment perspectives for patients with WLS.Abbreviations: BafA1: bafilomycin A1; ER: endoplasmic reticulum; HSPA9/GRP75: heat shock protein family A (Hsp70) member 9; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; MAM: mitochondria-associated endoplasmic reticulum membrane; MCU: mitochondrial calcium uniporter; MFN2: mitofusin 2; OCR: oxygen consumption rate; ROS: reactive oxygen species; ROT/AA: rotenone+antimycin A; VDAC1: voltage dependent anion channel 1; WLS: Wolfram-like syndrome; WS: Wolfram syndrome; WT: wild-type.

Glycinin (11S) and β-conglycinin (7S) from soybean (glycine max) cause diarrhea and intestinal barrier damage in young animals. Understanding the mechanisms underlying the damage caused by 7S and 11S, it is vital to develop strategies to eliminate allergenicity. Consequently, we investigated 7S/11S-mediated apoptosis in porcine intestinal epithelial (IPEC-J2) cells. IPEC-J2 cells suffered endoplasmic reticulum stress (ERS) in response to 7S and 11S, activating protein kinase RNA-like ER kinase, activating transcription factor 6, C/EBP homologous protein, and inositol-requiring enzyme 1 alpha. 4-Phenylbutyric acid (4-PBA) treatment alleviated ERS; reduced the NLR family pyrin domain containing 3, interleukin-1β, and interleukin-18 levels; inhibited apoptosis; increased mitofusin 2 expression; and mitigated Ca2+ overload and mitochondria-associated ER membrane (MAM) dysfunction, thereby ameliorating IPEC-J2 injury. We demonstrated the pivotal role of ERS in MAM dysfunction and 7S- and 11S-mediated apoptosis, providing insights into 7S- and 11S-mediated intestinal barrier injury prevention and treatment.

Vanadium (V) plays a crucial role in normal cells, but excess V causes multi-organ toxicity, including neurotoxicity. Mitochondria-associated endoplasmic reticulum membrane (MAM) is a dynamic structure between endoplasmic reticulum (ER) and mitochondria that mediates ER quality control (ERQC). To explore the effects of excess V on MAM and ERQC in the brain, 72 ducks were randomly divided into two groups: the control group (basal diet) and the V group (30 mg V/kg basal diet). On days 22 and 44, brain tissues were collected for histomorphological observation and determination of trace element contents. In addition, the mRNA and protein levels of MAM and ERQC-related factors in the brain were analyzed. Results show that excessive V causes the imbalance of trace elements, the integrity disruption of MAM, rupture of ER and autophagosomes formation. Moreover, it inhibits IP3R and VDAC1 co-localization, down-regulates the expression levels of MAM-related factors, but up-regulates the expression levels of ERQC and autophagy related factors. Together, results indicate that V exposure causes disruption of MAM and activates ERQC, which is further causing autophagy.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Mitochondrial dysfunction in renal tubules, occurring early in the disease, is linked to the development of DKD, although the underlying pathways remain unclear. Here, we examine diabetic human and mouse kidneys, and HK-2 cells exposed to high glucose, to show that high glucose disrupts mitochondria-associated endoplasmic reticulum membrane (MAM) and causes mitochondrial fragmentation. We find that high glucose conditions increase mitogen-activated protein kinase 1(MAPK1), a member of the MAP kinase signal transduction pathway, which in turn lowers the level of phosphofurin acidic cluster sorting protein 2 (PACS-2), a key component of MAM that tethers mitochondria to the ER. MAPK1-induced disruption of MAM leads to mitochondrial fragmentation but this can be rescued in HK-2 cells by increasing PACS-2 levels. Functional studies in diabetic mice show that inhibition of MAPK1 increases PACS-2 and protects against the loss of MAM and the mitochondrial fragmentation. Taken together, these results identify the MAPK1-PACS-2 axis as a key pathway to therapeutically target as well as provide new insights into the pathogenesis of DKD.

Vanadium (V) is an essential mineral element in animals, but excessive V can lead to many diseases, affecting the health of humans and animals. However, the molecular crosstalk between mitochondria-associated endoplasmic reticulum membranes (MAMs) and inflammation under V exposure is still at the exploratory stage. This study was conducted to determine the molecular crosstalk between MAMs and inflammation under V exposure in ducks. In this study, duck hepatocytes were treated with NaVO3 (0 μM, 100 μM, and 200 μM) and 2-aminoethyl diphenyl borate (2-APB) (IP3R inhibitor) alone or in combination for 24 h. The data showed that V exposure-induced cell vacuolization, enlarged intercellular space, and decreased density and viability. Meanwhile, hydrogen peroxide (H2O2), malonaldehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and reactive oxygen species (ROS) levels were upregulated under V treatment. In addition, excessive V could lead to a marked reduction in the MAMs structure, destruction of the membrane structure and overload of intracellular Ca2+ and mitochondrial Ca2+. Moreover, V treatment resulted in notable upregulation of the levels of MAMs-relevant factors (IP3R, Mfn2, Grp75, MCU, VDAC1) but downregulated the levels of IL-18, IL-1β, and lactate dehydrogenase (LDH) in the cell supernatant. Additionally, it also significantly elevated the levels of inflammation-relevant factors (NLRP3, ASC, caspase-1, MAVS, IL-18, IL-1β, and TXNIP). However, the inhibition of IP3R expression attenuated the V-induced variations in the above indicators. Collectively, our results revealed that the maintenance of calcium homeostasis could protect duck hepatocytes from V-induced inflammation injury via MAMs.

Copper (Cu) can be harmful to host physiology at high levels, although it is still unclear exactly how it causes nephrotoxicity. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are associated with heavy metal intoxication. Meanwhile, mitochondria and ER are connected via mitochondria-associated ER membranes (MAM). In order to reveal the crosstalk between them, a total of 144 1-day-old Peking ducks were randomly divided into four groups: control (basal diet), 100 mg/kg Cu, 200 mg/kg Cu, and 400 mg/kg Cu groups. Results found that excessive Cu disrupted MAM integrity, reduced the co-localization of IP3R and VDAC1, and significantly changed the MAM-related factors levels (Grp75, Mfn2, IP3R, MCU, PACS2, and VDAC1), leading to MAM dysfunction. We further found that Cu exposure induced mitochondrial dysfunction via decreasing the ATP level and the expression levels of COX4, TOM20, SIRT1, and OPA1 and up-regulating Parkin expression level. Meanwhile, Cu exposure dramatically increased the expression levels of Grp78, CRT, and ATF4, resulting in ER stress. Overall, these findings demonstrated MAM plays the critical role in Cu-induced kidney mitochondrial dysfunction and ER stress, which deepened our understanding of Cu-induced nephrotoxicity.