DIAPH1-MFN2 interaction regulates mitochondria-sarcoplasmic reticulum contact and modulates ischemic/hypoxic stress
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ABSTRACT:
PROVIDER: PRJNA884121 | ENA |
REPOSITORIES: ENA
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Project description:Inter-organelle contact and communication between mitochondria (Mito) and endoplasmic reticulum (ER), also known as sarcoplasmic reticulum (SR) in cardiomyocytes (CM), play vital roles in the maintenance of Mito and SR properties and cellular homeostasis. Here, we tested the hypothesis that the formin, Diaphanous-1 (DIAPH1), which regulates actin dynamics and signal transduction, contributes to these processes. Mice bearing CM-specific deletion of Diaph1 displayed reduced injury and superior functional recovery after the induction of cardiac ischemia and reperfusion (I/R). Studies in DIAPH1-silenced human induced pluripotent stem cell-derived CMs (HiPSC-CMs) and murine hearts devoid of CM-Diaph1 revealed that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to regulate Mito-SR contact, Mito turnover, mitophagy, and oxidative stress. Ischemic murine hearts and human heart biopsies revealed more robust DIAPH1-MFN2 interaction vs. that observed in non-ischemic hearts. Solution structure studies affirm this interaction and reveal strong pH-dependent interaction between the Diaphanous Inhibitory Domain (DID) and the cytosolic GTPase domain of MFN2. In HiPSC-CMs, introduction of synthetic linkers, which reduce the Mito-SR distance, mitigated the cardioprotective benefits of Diaph1 deletion. Finally, DIAPH1 binding to the cytoplasmic domain of receptor for advanced glycation endproduct (RAGE) supports signal transduction and contributes to I/R injury in the heart; in HiPSC-CMs, small molecule antagonism of RAGE-DIAPH1 reduced DIAPH1-MFN2 interaction and increased Mito-SR distance. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of Mito-SR contact networks that control responses to ischemic stress. Targeting pathways that regulate DIAPH1-MFN2 may facilitate recovery from cardiac ischemic injury.
2022-09-28 | GSE214149 | GEO
Project description:Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.
| S-EPMC10616211 | biostudies-literature
Project description:Organelles such as endoplasmic reticulum (ER) and mitochondria interact with each other at specialized domains on the ER known as mitochondria-associated membranes (MAMs). Here, using three-dimensional high-resolution imaging techniques, we show that the Sel1LHrd1 protein complex, the most conserved branch of ER-associated protein degradation (ERAD), exerts a profound impact on ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover and hence the abundance of the MAM protein sigma receptor 1 (SigmaR1). Sel1L or Hrd1 deficiency in brown adipocytes impairs dynamic interaction between ER and mitochondria, leading to the formation of pleomorphic “megamitochondria” and, in some cases with penetrating ER tubule(s), in response to acute cold challenge. Mice with ERAD deficiency are cold sensitive and exhibit mitochondrial dysfunction in brown adipocytes. Mechanistically, endogenous SigmaR1 is targeted for proteasomal degradation by Sel1L-Hrd1 ERAD, whose accumulation in ERAD-deficient cells leads to mitofusin 2 (Mfn2) oligomerization, thereby linking ERAD to mitochondrial dynamics. Our study identifies Sel1L-Hrd1 ERAD as a critical determinant of ER-mitochondria contacts, thereby regulating mitochondrial dynamics and thermogenesis.
2020-04-24 | GSE145895 | GEO
Project description:Cross linking of Diaphanous 1 inhibitory domain with Mitofusion 2 GTPase domain.
2023-10-26 | PXD045744 | JPOST Repository
Project description:Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.
2018-01-25 | MTBLS600 | MetaboLights
Project description:Maio et. al. presents a comprehensive and quantitative interactome of BZW2, a protein found to promote human cancers with little known about its molecular function. Many of the proteins identified were either mitochondrial or endoplasmic reticulum (ER) proteins, suggesting BZW2 may play a role in mitochondria-ER contact. We found that BZW2 indeed localizes to and promotes the formation of mitochondria-ER contact sites (MERCS), thus promoting calcium transport from ER to the mitochondria and promotes mitochondrial ATP production. These findings provide key insights into molecular functions of BZW2, the potential role of BZW2 in cancer progression, and highlights the utility of interactome data in understanding the function of less-studied proteins.
2024-05-24 | PXD041354 | Pride
Project description:Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER encounter structure (ERMES) and Tom70 are part of two cooperative and partially redundant ER-to-mitochondria transfer routes. If the ER-to-mitochondria transfer is prevented, many mitochondrial precursor proteins accumulate non-productively on the ER surface, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.
2024-03-05 | PXD044379 | Pride
Project description:The Endoplasmic Reticulum–Mitochondria Encounter Structure (ERMES) is a protein complex that tethers the two organelles and creates the physical basis for communication between them. ERMES functions in lipid and calcium exchange between the ER and mitochondria, mitochondrial protein import and maintenance of mitochondrial morphology and genome. Here we report that ERMES is also required for iron homeostasis. Loss of ERMES components activates an Aft1-dependent iron deficiency response even in iron-replete conditions, leading to accumulation of excess iron inside the cell. This function is independent of ERMES known roles in calcium regulation, phospholipid biosynthesis or mitochondrial biology. A mutation in the vacuolar protein sorting 13 (VPS13) gene that rescues the glycolytic phenotype of ERMES mutants suppresses the iron deficiency response and iron accumulation. Our study reveals that proper communication between the ER and mitochondria is required for appropriate maintenance of cellular iron levels.
2017-06-20 | GSE99499 | GEO
Project description:Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also regulate systemic functions remains unknown. Here, we report the ultrastructural organization and dynamics of the inter-organellar contact established by rough-Endoplasmic Reticulum closely wrapped around the mitochondria (wrappER). To elucidate the in vivo function of this contact, mouse liver fractions enriched in wrappER-associated-mitochondria are analyzed by transcriptomics, proteomics and lipidomics. The biochemical signature of the wrappER points to a role in the biogenesis of very-low-density lipoproteins (VLDL). Altering wrappER-mitochondria contacts curtails VLDL secretion and increases hepatic fatty acids, lipid droplets and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, recapitulates this hepatic dyslipidemia phenotype and promotes remodelling of the wrappER-mitochondria contact. The discovery that liver wrappER-mitochondria contacts participate in VLDL biology suggests an involvement of inter-organelle contacts in systemic lipid homeostasis.
2021-03-15 | GSE134777 | GEO
Project description:Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER encounter structure (ERMES) and Tom70 are part of two cooperative and partially redundant ER-to-mitochondria transfer routes. If the ER-to-mitochondria transfer is prevented, many mitochondrial precursor proteins accumulate non-productively on the ER surface, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.
2024-03-05 | PXD044362 | Pride