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Stasimon/Tmem41b localizes to mitochondria-associated ER membranes and is essential for mouse embryonic development.

ABSTRACT: Stasimon (also known as Tmem41b) is an evolutionarily conserved transmembrane protein first identified for its contribution to motor system dysfunction in animal models of the childhood neurodegenerative disease spinal muscular atrophy (SMA). Stasimon was shown to be required for normal neurotransmission in the motor circuit of Drosophila larvae and proper development of motor axons in zebrafish embryos as well as to suppress analogous neuronal phenotypes in SMA models of these organisms. However, the subcellular localization and molecular functions of Stasimon are poorly understood. Here, we combined immunoprecipitation with mass spectrometry to characterize the Stasimon interactome in mammalian cells, which reveals association with components of the endoplasmic reticulum (ER), mitochondria, and the COPI vesicle trafficking machinery. Expanding on the interaction results, we used subcellular fractionation studies and super-resolution microscopy to identify Stasimon as an ER-resident protein that localizes at mitochondria-associated ER membranes (MAM), functionally specialized contact sites between ER and mitochondria membranes. Lastly, through characterization of novel knockout mice, we show that Stasimon is an essential gene for mouse embryonic development. Together, these findings identify Stasimon as a novel transmembrane protein component of the MAM with an essential requirement for mammalian development.

SUBMITTER: Van Alstyne M

PROVIDER: S-EPMC6242727 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Stasimon/Tmem41b localizes to mitochondria-associated ER membranes and is essential for mouse embryonic development.

Van Alstyne Meaghan M Lotti Francesco F Dal Mas Andrea A Area-Gomez Estela E Pellizzoni Livio L

Biochemical and biophysical research communications 20181022 3

Stasimon (also known as Tmem41b) is an evolutionarily conserved transmembrane protein first identified for its contribution to motor system dysfunction in animal models of the childhood neurodegenerative disease spinal muscular atrophy (SMA). Stasimon was shown to be required for normal neurotransmission in the motor circuit of Drosophila larvae and proper development of motor axons in zebrafish embryos as well as to suppress analogous neuronal phenotypes in SMA models of these organisms. Howeve ...[more]

PMID: 30352685

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Project description:BackgroundDiabetes is associated with an increased risk of cognitive decline and dementia. These diseases are linked with mitochondrial dysfunction, most likely as a consequence of excessive formation of mitochondria-associated membranes (MAMs). Sirtuin3 (SIRT3), a key mitochondrial NAD+-dependent deacetylase, is critical responsible for mitochondrial functional homeostasis and is highly associated with neuropathology. However, the role of SIRT3 in regulating MAM coupling remains unknown.MethodsStreptozotocin-injected diabetic mice and high glucose-treated SH-SY5Y cells were established as the animal and cellular models, respectively. SIRT3 expression was up-regulated in vivo using an adeno-associated virus in mouse hippocampus and in vitro using a recombinant lentivirus vector. Cognitive function was evaluated using behavioural tests. Hippocampus injury was assessed using Golgi and Nissl staining. Apoptosis was analysed using western blotting and TUNEL assay. Mitochondrial function was detected using flow cytometry and confocal fluorescence microscopy. The mechanisms were investigated using co-immunoprecipitation of VDAC1-GRP75-IP3R complex, fluorescence imaging of ER and mitochondrial co-localisation and transmission electron microscopy of structural analysis of MAMs.ResultsOur results demonstrated that SIRT3 expression was significantly reduced in high glucose-treated SH-SY5Y cells and hippocampal tissues from diabetic mice. Further, up-regulating SIRT3 alleviated hippocampus injuries and cognitive impairment in diabetic mice and mitigated mitochondrial Ca2+ overload-induced mitochondrial dysfunction and apoptosis. Mechanistically, MAM formation was enhanced under high glucose conditions, which was reversed by genetic up-regulation of SIRT3 via reduced interaction of the VDAC1-GRP75-IP3R complex in vitro and in vivo. Furthermore, we investigated the therapeutic effects of pharmacological activation of SIRT3 in diabetic mice via honokiol treatment, which exhibited similar effects to our genetic interventions.ConclusionsIn summary, our findings suggest that SIRT3 ameliorates cognitive impairment in diabetic mice by limiting aberrant MAM formation. Furthermore, targeting the activation of SIRT3 by honokiol provides a promising therapeutic candidate for diabetes-associated cognitive dysfunction. Overall, our study suggests a novel role of SIRT3 in regulating MAM coupling and indicates that SIRT3-targeted therapies are promising for diabetic dementia patients.

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Stasimon/Tmem41b localizes to mitochondria-associated ER membranes and is essential for mouse embryonic development.

Publications

Stasimon/Tmem41b localizes to mitochondria-associated ER membranes and is essential for mouse embryonic development.

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