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      Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fission

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          Abstract

          Mitochondrial morphology is controlled by two opposing processes: fusion and fission. Drp1 (dynamin-related protein 1) and hFis1 are two key players of mitochondrial fission, but how Drp1 is recruited to mitochondria and how Drp1-mediated mitochondrial fission is regulated in mammals is poorly understood. Here, we identify the vertebrate-specific protein MIEF1 (mitochondrial elongation factor 1; independently identified as MiD51), which is anchored to the outer mitochondrial membrane. Elevated MIEF1 levels induce extensive mitochondrial fusion, whereas depletion of MIEF1 causes mitochondrial fragmentation. MIEF1 interacts with and recruits Drp1 to mitochondria in a manner independent of hFis1, Mff (mitochondrial fission factor) and Mfn2 (mitofusin 2), but inhibits Drp1 activity, thus executing a negative effect on mitochondrial fission. MIEF1 also interacts with hFis1 and elevated hFis1 levels partially reverse the MIEF1-induced fusion phenotype. In addition to inhibiting Drp1, MIEF1 also actively promotes fusion, but in a manner distinct from mitofusins. In conclusion, our findings uncover a novel mechanism which controls the mitochondrial fusion–fission machinery in vertebrates. As MIEF1 is vertebrate-specific, these data also reveal important differences between yeast and vertebrates in the regulation of mitochondrial dynamics.

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          Most cited references 25

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          Mitochondrial dynamics and apoptosis.

          In healthy cells, mitochondria continually divide and fuse to form a dynamic interconnecting network. The molecular machinery that mediates this organelle fission and fusion is necessary to maintain mitochondrial integrity, perhaps by facilitating DNA or protein quality control. This network disintegrates during apoptosis at the time of cytochrome c release and prior to caspase activation, yielding more numerous and smaller mitochondria. Recent work shows that proteins involved in mitochondrial fission and fusion also actively participate in apoptosis induction. This review will cover the recent advances and presents competing models on how the mitochondrial fission and fusion machinery may intersect apoptosis pathways.
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            Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice.

            Mitochondrial morphology is dynamically controlled by a balance between fusion and fission. The physiological importance of mitochondrial fission in vertebrates is less clearly defined than that of mitochondrial fusion. Here we show that mice lacking the mitochondrial fission GTPase Drp1 have developmental abnormalities, particularly in the forebrain, and die after embryonic day 12.5. Neural cell-specific (NS) Drp1(-/-) mice die shortly after birth as a result of brain hypoplasia with apoptosis. Primary culture of NS-Drp1(-/-) mouse forebrain showed a decreased number of neurites and defective synapse formation, thought to be due to aggregated mitochondria that failed to distribute properly within the cell processes. These defects were reflected by abnormal forebrain development and highlight the importance of Drp1-dependent mitochondrial fission within highly polarized cells such as neurons. Moreover, Drp1(-/-) murine embryonic fibroblasts and embryonic stem cells revealed that Drp1 is required for a normal rate of cytochrome c release and caspase activation during apoptosis, although mitochondrial outer membrane permeabilization, as examined by the release of Smac/Diablo and Tim8a, may occur independently of Drp1 activity.
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              Mitochondrial dynamics in mammalian health and disease.

              The meaning of the word mitochondrion (from the Greek mitos, meaning thread, and chondros, grain) illustrates that the heterogeneity of mitochondrial morphology has been known since the first descriptions of this organelle. Such a heterogeneous morphology is explained by the dynamic nature of mitochondria. Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. Furthermore, during the last decade, it has been identified that mutations in two mitochondrial fusion genes (MFN2 and OPA1) cause prevalent neurodegenerative diseases (Charcot-Marie Tooth type 2A and Kjer disease/autosomal dominant optic atrophy). In addition, other diseases such as type 2 diabetes or vascular proliferative disorders show impaired MFN2 expression. Altogether, these findings have established mitochondrial dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies.
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                Author and article information

                Journal
                EMBO J
                The EMBO Journal
                Nature Publishing Group
                0261-4189
                1460-2075
                20 July 2011
                24 June 2011
                24 June 2011
                : 30
                : 14
                : 2762-2778
                Affiliations
                [1 ]Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna , Stockholm, Sweden
                [2 ]Department of Cell and Molecular Biology, Karolinska Institutet , Stockholm, Sweden
                [3 ]Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm, Sweden
                [4 ]Department of Neuroscience, Karolinska Institutet , Stockholm, Sweden
                Author notes
                [a ]Department of Oncology-Pathology, Karolinska Institutet, CCK R8:05, Karolinska University Hospital Solna, Stockholm SE-17176, Sweden. Tel.: +46 8 51776640; Fax: +46 8 321047; E-mail: jian.zhao@ 123456ki.se
                [b ]Department of Oncology-Pathology, Karolinska Institutet, CCK R8:05, Karolinska University Hospital Solna, Stockholm SE-17176, Sweden. Tel.: +46 8 51770309; Fax: +46 8 321047; monica.nister@ 123456ki.se
                [c ]Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm SE-17177, Sweden. Tel.: +46 8 52487323; Fax: +46 8 52487301; E-mail: urban.lendahl@ 123456ki.se
                [*]

                These authors contributed equally to this work

                Article
                emboj2011198
                10.1038/emboj.2011.198
                3160255
                21701560
                Copyright © 2011, European Molecular Biology Organization

                This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial Share Alike 3.0 Unported License, which allows readers to alter, transform, or build upon the article and then distribute the resulting work under the same or similar license to this one. The work must be attributed back to the original author and commercial use is not permitted without specific permission.

                Categories
                Article

                Molecular biology

                smcr7l, mitochondrial fusion and fission, mief1/mid51, hfis1, drp1

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