The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells

Tondera, Daniel; Czauderna, Frank; Paulick, Katharina; Schwarzer, Rolf; Kaufmann, Jörg; Santel, Ansgar

doi:10.1242/jcs.02415

Cited by 199 publications

(162 citation statements)

References 47 publications

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“…A mutated form of this protein with dominantnegative activity (Drp1K38A) localizes in large cytoplasmic aggregates, blocks mitochondrial fission and induces a formation of tubular morphotypes. [19][20][21] Visual inspection of cells coexpressing G72 and Drp1K38A revealed that mitochondrial fragmentation is drastically reduced ( Figure 3C, a-d). Quantification of mitochondrial morphology indeed revealed a large reduction of fragmented morphotypes and accumulation of mixed morphotypes in G72/Drp1K38A cotransfected cells as compared to G72-transfected cells (P < 0.0001).…”

Section: Increase In G72 Levels Results In Mitochondrial Fragmentatiomentioning

confidence: 99%

Evidence implicating the candidate schizophrenia/bipolar disorder susceptibility gene G72 in mitochondrial function

et al. 2007

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G72 is a strong candidate susceptibility gene for schizophrenia and bipolar disorder, whose function remains enigmatic. Here we show that one splicing isoform of the gene (LG72 ) encodes for a mitochondrial protein. We also provide convergent lines of evidence that increase of endogenous or exogenous G72 levels promotes robust mitochondrial fragmentation in mammalian cell lines and primary neurons, which proceeds in a manner that does not depend on induction of apoptosis or alteration in mitochondrial transmembrane potential. Finally, we show that increase in G72 levels in immature primary neurons is accompanied by a marked increase in dendritic arborization. By contrast, we failed to confirm the originally proposed functional interaction between G72 and D-amino acid oxidase (DAO) in two tested cell lines. Our results suggest an alternative role for G72 in modulating mitochondrial function.

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Section: Increase In G72 Levels Results In Mitochondrial Fragmentatiomentioning

confidence: 99%

Evidence implicating the candidate schizophrenia/bipolar disorder susceptibility gene G72 in mitochondrial function

et al. 2007

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“…To date, few actors of the IMM dynamic have been identified in mammal cells, among them the MTP18 protein, 29 the mitofilin 30 and OPA1. The fact that the OPA1 protein exists as eight different isoforms in vertebrates suggests that these proteins can fulfil different functions inside mitochondria.…”

Section: Discussionmentioning

confidence: 99%

OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis

et al. 2006

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In most eucaryote cells, release of apoptotic proteins from mitochondria involves fission of the mitochondrial network and drastic remodelling of the cristae structures. The intramitochondrial dynamin OPA1, as a potential central actor of these processes, exists as eight isoforms resulting from the alternate splicing combinations of exons (Ex) 4, 4b and 5b, which functions remain undetermined. Here, we show that Ex4 that is conserved throughout evolution confers functions to OPA1 involved in the maintenance of the DW m and in the fusion of the mitochondrial network. Conversely, Ex4b and Ex5b, which are vertebrate specific, define a function involved in cytochrome c release, an apoptotic process also restricted to vertebrates. The drastic changes of OPA1 variant abundance in different organs suggest that nuclear splicing can control mitochondrial dynamic fate and susceptibility to apoptosis and pathologies. Mitochondrial membrane dynamics, involving both the fusionfission of the mitochondrial network and remodelling of cristae structures, are essential processes in cellular adaptation to changes of growth condition and programmed cell death. [1][2][3] The outer and inner mitochondrial membrane (OMM and IMM) dynamics crosstalk and involve large GTPases: respectively, the mitofusins Mfn1 and Mfn2 4,5 and the dynamin-related DRP1 6 on the OMM, and the dynaminrelated OPA1, localized in the inter membrane space (IMS). 7 Mitochondrial fission is tightly associated to the apoptotic process, and physical and functional interactions between apoptotic proteins including Bcl2-homologue domains and DRP1 and mitofusins have been identified. 8 In addition, BH3-only proapoptotic proteins, exemplified by tBid and Bik, might act directly on the IMM structure, although their intramitochondrial target remains unknown. 3,9 Further crosstalk between the OMM and the IMM is exemplified by the OMM fission and fusion regulation by the mitochondrial membrane potential (DC m ) 10 and structural integrity 11 and by interaction between OPA1 and Mfn1. 12 The IMM forms, an architecturally complex structure, that has been reconsidered recently in the light of tomography analysis associated to transmission electron microscopy (TEM). Indeed, tubular inner membrane junctions, called cristae junctions, have been evidenced between the IMM facing the OMM and the vesicular-shaped cristae. 13 In vertebrate cells, during the apoptotic process, the cristae junction topology is drastically modified to mobilize cytochrome c (cyt c) from the intracristae compartment to the IMS, before its extensive release in the cytoplasm. 3,9 How this process is physically controlled and related to the OMM dynamic remains unknown. We and others have shown that OPA1 is a good candidate for the regulation of the cristae structure in the mitochondria. 11,14 Indeed, downregulation of OPA1 affect the IMM structure and integrity, leading to respiration defects and DC m loss, fission of the mitochondrial network, impairment of growth and apoptosis 11,14-18 and OPA1 overexpressio...

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“…A less well characterized protein, MTP18, is a fission factor embedded in the IMM that is conserved in metazoans [46]. Genetic deletion of this protein results in hyperfused mitochondria and overexpression results in excessive mitochondrial fission.…”

Section: Inner Mitochondrial Membrane Fission and Fusionmentioning

confidence: 99%

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

Ali

McStay

2017

Preprint

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The mitochondrial network is a dynamic organization within eukaryotic cells that participates in a variety of essential cellular processes, such as ATP synthesis, central metabolism, apoptosis and inflammation. The mitochondrial network is balanced between rates of fusion and fission that respond to pathophysiologic signals to coordinate appropriate mitochondrial processes. Mitochondrial fusion and fission are regulated by proteins that either reside or translocate to the inner or outer mitochondrial membranes or are soluble in the inter-membrane space. Mitochondrial fission and fusion are performed by GTPases on the outer and inner mitochondrial membranes with the assistance of other mitochondrial proteins. Due to the essential nature of mitochondrial function for cellular homeostasis regulation of mitochondrial dynamics is under strict control. Some of the mechanisms used to regulate the function of these proteins are post-translational proteolysis and/or turnover and this review will discuss these mechanisms required for correct mitochondrial network organization. IntroductionMitochondria are the power houses of every nucleated cell, generating chemical energy in the form of adenosine triphosphate (ATP) by the oxidative phosphorylation (OXPHOS) system. Mitochondria are also important for the normal functioning of the cells as they regulate several crucial activities like differentiation, cell cycle, intracellular signaling and cell death [1]. Mitochondria are unique because of their autonomous DNA (mtDNA), which encodes for proteins required for ATP synthesis. Therefore maintenance of mtDNA is important for normal mitochondrial function and for the diversity of mitochondrial genome [2]. Mitochondria form elongated tubules that continually divide and fuse to form a complex, interconnected and highly dynamic network inside of cells. These dynamics processes not only regulate mitochondrial function but also mitochondrial shape, content exchange and mitochondrial communication with the cytoskeleton [3]. Due to the involvement of mitochondria in a large spectrum of cellular functions, these organelles play a key role in mediating cellular homeostasis. As a result a healthy population of mitochondria is critical for cell survival.

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The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells

Cited by 199 publications

References 47 publications

Evidence implicating the candidate schizophrenia/bipolar disorder susceptibility gene G72 in mitochondrial function

Evidence implicating the candidate schizophrenia/bipolar disorder susceptibility gene G72 in mitochondrial function

OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

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