Mitochondria-Associated Organelle Crosstalk in Myocardial Ischemia/Reperfusion Injury.

Organelle damage is a significant contributor to myocardial ischemia/reperfusion (I/R) injury. This damage often leads to disruption of endoplasmic reticulum protein regulatory programs and dysfunction of mitochondrial energy metabolism. Mitochondria and endoplasmic reticulum are seamlessly connected through the mitochondrial-associated endoplasmic reticulum membrane (MAM), which serves as a crucial site for the exchange of organelles and metabolites. However, there is a lack of reports regarding the communication of information and metabolites between mitochondria and related organelles, which is a crucial factor in triggering myocardial I/R damage. To address this research gap, this review described the role of crosstalk between mitochondria and the correlative organelles such as endoplasmic reticulum, lysosomal and nuclei involved in reperfusion injury of the heart. In summary, this review aims to provide a comprehensive understanding of the crosstalk between organelles in myocardial I/R injury, with the ultimate goal of facilitating the development of targeted therapies based on this knowledge.

Ip3r-Grp75-Vdac and Relevant Ca2+ Signaling Regulate Dietary Palmitic Acid-Induced De Novo Lipogenesis by Mitochondria-Associated ER Membrane (MAM) Recruiting Seipin in Yellow Catfish.

BACKGROUND: The mitochondria-associated endoplasmic reticulum membrane (MAM) is the central hub for endoplasmic reticulum and mitochondria functional communication. It plays a crucial role in hepatic lipid homeostasis. However, even though MAM has been acknowledged to be rich in enzymes that contribute to lipid biosynthesis, no study has yet investigated the exact role of MAM on hepatic neutral lipid synthesis. OBJECTIVES: To address these gaps, this study investigated the systemic control mechanisms of MAM on neutral lipids synthesis by recruiting seipin, focusing on the role of the inositol trisphosphate receptor-1,4,5(Ip3r)-75 kDa glucose-regulated protein (Grp75)-voltage-dependent anion channel (Vdac) complex and their relevant Ca2+ signaling in this process. METHODS: To this end, a model animal for lipid metabolism, yellow catfish (Pelteobagrus fulvidraco), were fed 6 different diets containing a range of palmitic acid (PA) concentrations from 0-150 g/kg in vivo for 10 wk. In vitro, experiments were also conducted to intercept the MAM-mediated Ca2+ signaling in isolated hepatocytes by transfecting them with si-mitochondrial calcium uniporter (mcu). Because mcu was placed in the inner mitochondrial membrane (IMM), si-mcu cannot disrupt MAM's structural integrity. RESULTS: 1. Hepatocellular MAM subproteome analysis indicated excessive dietary PA intake enhanced hepatic MAM structure joined by activating Ip3r-Grp75-Vdac complexes. 2. Dietary PA intake induced hepatic neutral lipid accumulation through MAM recruiting Seipin, which activated lipid droplet biogenesis. Our findings also revealed a previously unidentified mechanism whereby MAM-recruited seipin and controlled hepatic lipid homeostasis, depending on Ip3r-Grp75-Vdac-controlled Ca2+ signaling and not only MAM's structural integrity. CONCLUSIONS: These results offer a novel insight into the MAM-recruited seipin in controlling hepatic lipid synthesis in a MAM structural integrity-dependent and Ca2+ signaling-dependent manner, highlighting the critical contribution of MAM in maintaining hepatic neutral lipid homeostasis.

Broadening horizons: the contribution of mitochondria-associated endoplasmic reticulum membrane (MAM) dysfunction in diabetic kidney disease.

Diabetic kidney disease (DKD) is a global health issue that presents a complex pathogenesis and limited treatment options. To provide guidance for precise therapies, it is crucial to accurately identify the pathogenesis of DKD. Several studies have recognized that mitochondrial and endoplasmic reticulum (ER) dysfunction are key drivers of the pathogenesis of DKD. The mitochondria-associated ER membrane (MAM) is a dynamic membrane contact site (MSC) that connects the ER and mitochondria and is essential in maintaining the normal function of the two organelles. MAM is involved in various cellular processes, including lipid synthesis and transport, calcium homeostasis, mitochondrial fusion and fission, and ER stress. Meanwhile, recent studies confirm that MAM plays a significant role in the pathogenesis of DKD by regulating glucose metabolism, lipid metabolism, inflammation, ER stress, mitochondrial fission and fusion, and autophagy. Herein, this review aims to provide a comprehensive summary of the physiological function of MAMs and their impact on the progression of DKD. Subsequently, we discuss the trend of pharmaceutical studies that target MAM resident proteins for treating DKD. Furthermore, we also explore the future development prospects of MAM in DKD research, thereby providing a new perspective for basic studies and clinical treatment of DKD.

SIGMAR1 Confers Innate Resilience against Neurodegeneration.

The sigma-1 receptor (SIGMAR1) is one of a kind: a receptor chaperone protein. This 223 amino acid-long protein is enriched at the mitochondria-associated endoplasmic reticulum membrane (MAM), a specialized microdomain of the endoplasmic reticulum that is structurally and functionally connected to the mitochondria. As a receptor, SIGMAR1 binds a wide spectrum of ligands. Numerous molecules targeting SIGMAR1 are currently in pre-clinical or clinical development. Interestingly, the range of pathologies covered by these studies is broad, especially with regard to neurodegenerative disorders. Upon activation, SIGMAR1 can translocate and interact with other proteins, mostly at the MAM but also in other organelles, which allows SIGMAR1 to affect many cellular functions. During these interactions, SIGMAR1 exhibits chaperone protein behavior by participating in the folding and stabilization of its partner. In this short communication, we will shed light on how SIGMAR1 confers protection against neurodegeneration to the cells of the nervous system and why this ability makes SIGMAR1 a multifunctional therapeutic prospect.

PRE-084 ameliorated learning and memory impairment in T1DM via regulating neuronal MAM / 西安交通大学学报(医学版)

【Objective】 Diabetic mice could show learning and memory dysfunction, and we aimed to investigate the effect of Sigma-1 receptor agonist, PRE-084, on neurons and cognitive impairment in mice with type 1 diabetes (T1DM). 【Methods】 Twenty mice with T1DM induced by streptozocin, aged 8-10 weeks, and 20 control mice (CON) were randomly divided into four groups (CON+Vehicle, CON+PRE-084, T1DM+Vehicle and T1DM+PRE-084). Mouse primary neurons were cultured in high glucose medium with PRE-084 and control solvent, respectively. The body weight, food and water intake, and fasting blood glucose level of mice in each group were detected and recorded. The learning and memory abilities of mice were detected by new object recognition experiment. The mitochondria-associated endoplasmic reticulum membrane (MAM) structure of neurons in hippocampal CA1 area of mice was detected by transmission electron microscope. And the expression levels of ATP and reactive oxygen species (ROS) in hippocampus of mice were detected by biochemical kit. Cell viability and ROS level of primary neurons were detected by CCK8 and cellular ROS kit. 【Results】 PRE-084 reduced the increase of body weight, food and water intake, and blood glucose caused by diabetes. PRE-084 significantly ameliorated the learning and memory impairment of the mice with T1DM, improved the changes of MAM structure in neurons of hippocampal CA1 area of diabetic mice, increased the level of ATP in hippocampus of diabetic mice, and decreased the increase of ROS expression in diabetic hippocampus and neurons under high glucose conditions. 【Conclusion】 Sigma-1 receptor agonist, PRE-084, could improve learning and memory impairment in the mice with T1DM, which might be related to the structural changes of MAM, the increase of ATP production, and the decrease of ROS production in hippocampal neurons.

Activation of endoplasmic reticulum-mitochondria coupling drives copper-induced autophagy in duck renal tubular epithelial cells.

Copper (Cu) as a transition metal can be toxic to public and ecosystem health at high level, but the specific mechanism of Cu-evoked nephrotoxicity remains elusive. Here, we first revealed the crosstalk between mitofusin2 (Mfn2)-dependent mitochondria-associated endoplasmic reticulum membrane (MAM) dynamics and autophagy in duck renal tubular epithelial cells under Cu exposure. Primary duck renal tubular epithelial cells were treated with 100 and 200 µM Cu sulfate for 12 h and exposed to lentivirus to deliver mitofusin2 (Mfn2). We found that excessive Cu disrupted MAM integrity, decreased the mitochondrial calcium level, co-localization of IP3R and VDAC1, the mRNA levels of PACS2, Mfn2, IP3R and MCU, and Mfn2 and VDAC1 protein levels, causing MAM dysfunction. Furthermore, Mfn2 overexpression ameliorated Cu-induced MAM dysfunction, and increased Cu-evoked autophagy in duck renal tubular epithelial cells accompanied with the elevation of autophagosomes number, ROS level, LC3 puncta, Atg5 and LC3B mRNA levels, and Beclin1, Atg14, LC3BII/LC3BI protein levels. Accordingly, our data proved that excessive Cu could trigger MAM dysfunction and autophagy in duck renal tubular epithelial cells, and Cu-induced autophagy could be activated through Mfn2-dependent MAM, providing evidence on the toxicological exploration mechanisms of Cu.

Systematic In-Depth Proteomic Analysis of Mitochondria-Associated Endoplasmic Reticulum Membranes in Mouse and Human Testes.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) regulate important cellular functions including calcium signaling, bioenergetics, and apoptosis during neurodevelopment and carcinogenesis, but its function in male reproduction and spermatogenesis remains enigmatic because the field lacks a complete understanding of the proteome within testis MAMs. To better understand the biological processes and molecular functions of MAM in testes, a global mass spectrometry-based proteomic evaluation of MAM proteins from human and mouse testes are reported here, respectively. The evaluation and analysis showed that the components of MAM were highly conserved not only between different species (human and mouse) but also between different tissues (testes and brains). Bioinformatics interrogation of these MAM protein catalogues uncovered that 815 new potential linkages specifically existed in mouse testes compared with mouse brains. In addition, a comparative analysis showed that 1347 proteins (account for ≈96.56%) were highly conservatively expressed in both human and mouse testis MAMs. Furthermore, functional analysis revealed that testis-specific MAM proteins were related to spermatogenesis, male gamete generation, as well as sexual reproduction. The data identified, for the first time, numerous MAM proteins in mouse and human testes, which provide a possibility to define the relationship between testis MAM proteins and reproductive diseases.