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Mdv1p is a WD repeat protein that interacts with the dynamin-related GTPase, Dnm1p, to trigger mitochondrial division.

Tieu Q, Nunnari J - J. Cell Biol. (2000)

Bottom Line: Whereas localization of Mdv1p to these structures requires Dnm1p, localization of Mdv1p to mitochondrial membranes does not.Dnm1p-independent targeting of Mdv1p to mitochondria requires MDV2.Our data indicate that MDV2 also functions separately to regulate the assembly of Dnm1p into punctate structures.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular and Cellular Biology, University of California Davis, Davis, California 95616, USA.

ABSTRACT
Mitochondrial fission is mediated by the dynamin-related GTPase, Dnm1p, which assembles on the mitochondrial outer membrane into punctate structures associated with sites of membrane constriction and fission. We have identified additional nuclear genes required for mitochondrial fission, termed MDV (for mitochondrial division). MDV1 encodes a predicted soluble protein, containing a coiled-coil motif and seven COOH-terminal WD repeats. Genetic and two-hybrid analyses indicate that Mdv1p interacts with Dnm1p to mediate mitochondrial fission. In addition, Mdv1p colocalizes with Dnm1p in fission-mediating punctate structures on the mitochondrial outer membrane. Whereas localization of Mdv1p to these structures requires Dnm1p, localization of Mdv1p to mitochondrial membranes does not. This indicates that Mdv1p possesses a Dnm1p-independent mitochondrial targeting signal. Dnm1p-independent targeting of Mdv1p to mitochondria requires MDV2. Our data indicate that MDV2 also functions separately to regulate the assembly of Dnm1p into punctate structures. In contrast, Mdv1p is not required for the assembly of Dnm1p, but Dnm1p-containing punctate structures lacking Mdv1p are not able to complete division. Our studies suggest that mitochondrial fission is a multi-step process in which Mdv2p regulates the assembly of Dnm1p into punctate structures and together with Mdv1p functions later during fission to facilitate Dnm1p-dependent mitochondrial membrane constriction and/or division.

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Schematic model of the mitochondrial fission pathway. Mitochondrial tubules are diagramed in cross-section and red circles represent Dnm1p. Mitochondrial fission is initiated by the recruitment of Dnm1p from the cytosol to the mitochondrial membrane by an unknown regulatory mechanism (1). In a Fis1p-dependent regulated manner, mitochondrial-associated Dnm1p subsequently assembles into higher order structures that possibly form rings around the surface of the mitochondrial outer membrane (2). Via a direct interaction with Dnm1p, Mdv1p either coassembles with Dnm1p during the formation of these higher order structures or associates with Dnm1p in these structures after their formation. Mdv1p functions to recruit either Fis1p or a Fis1p-dependent component to the Mdv1p/Dnm1p structure, thereby catalyzing the potentially rate-limiting steps of membrane constriction (3) and membrane division (4).
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Figure 12: Schematic model of the mitochondrial fission pathway. Mitochondrial tubules are diagramed in cross-section and red circles represent Dnm1p. Mitochondrial fission is initiated by the recruitment of Dnm1p from the cytosol to the mitochondrial membrane by an unknown regulatory mechanism (1). In a Fis1p-dependent regulated manner, mitochondrial-associated Dnm1p subsequently assembles into higher order structures that possibly form rings around the surface of the mitochondrial outer membrane (2). Via a direct interaction with Dnm1p, Mdv1p either coassembles with Dnm1p during the formation of these higher order structures or associates with Dnm1p in these structures after their formation. Mdv1p functions to recruit either Fis1p or a Fis1p-dependent component to the Mdv1p/Dnm1p structure, thereby catalyzing the potentially rate-limiting steps of membrane constriction (3) and membrane division (4).

Mentions: We have identified two genes, MDV1 and MDV2, that function with DNM1 to mediate mitochondrial fission. Our analysis of mdv1 and mdv2 cells, together with biochemical and ultrastructural analyses of the subcellular localization of Dnm1p, indicate that mitochondrial fission is a multi-step pathway, regulated by Mdv1p and Mdv2p, and similar in mechanism to dynamin-mediated endocytosis (Fig. 12; Otsuga et al. 1998; Schmid et al. 1998; Bleazard et al. 1999; Labrousse et al. 1999; Sesaki and Jensen 1999; Sever et al. 2000). These data support a model where Dnm1p is initially recruited from the cytosol to the mitochondrial outer membrane, where it subsequently assembles into punctate structures that ultimately mediate the division of mitochondrial membranes (Fig. 12, steps 1 and 2). Immunoelectron microscopy indicates that Dnm1p puncta are found at sites where the inner and outer mitochondrial membranes are coordinately constricted, and also on tubule tips that are presumably the end products of the division reaction (Bleazard et al. 1999). Because only a fraction of Dnm1p-containing structures are associated with constriction sites at steady state, it is probable that Dnm1p-mediated mitochondrial membrane constriction and/or mitochondrial membrane division are the rate-limiting steps in this pathway (Fig. 12, steps 3 and 4).


Mdv1p is a WD repeat protein that interacts with the dynamin-related GTPase, Dnm1p, to trigger mitochondrial division.

Tieu Q, Nunnari J - J. Cell Biol. (2000)

Schematic model of the mitochondrial fission pathway. Mitochondrial tubules are diagramed in cross-section and red circles represent Dnm1p. Mitochondrial fission is initiated by the recruitment of Dnm1p from the cytosol to the mitochondrial membrane by an unknown regulatory mechanism (1). In a Fis1p-dependent regulated manner, mitochondrial-associated Dnm1p subsequently assembles into higher order structures that possibly form rings around the surface of the mitochondrial outer membrane (2). Via a direct interaction with Dnm1p, Mdv1p either coassembles with Dnm1p during the formation of these higher order structures or associates with Dnm1p in these structures after their formation. Mdv1p functions to recruit either Fis1p or a Fis1p-dependent component to the Mdv1p/Dnm1p structure, thereby catalyzing the potentially rate-limiting steps of membrane constriction (3) and membrane division (4).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2192646&req=5

Figure 12: Schematic model of the mitochondrial fission pathway. Mitochondrial tubules are diagramed in cross-section and red circles represent Dnm1p. Mitochondrial fission is initiated by the recruitment of Dnm1p from the cytosol to the mitochondrial membrane by an unknown regulatory mechanism (1). In a Fis1p-dependent regulated manner, mitochondrial-associated Dnm1p subsequently assembles into higher order structures that possibly form rings around the surface of the mitochondrial outer membrane (2). Via a direct interaction with Dnm1p, Mdv1p either coassembles with Dnm1p during the formation of these higher order structures or associates with Dnm1p in these structures after their formation. Mdv1p functions to recruit either Fis1p or a Fis1p-dependent component to the Mdv1p/Dnm1p structure, thereby catalyzing the potentially rate-limiting steps of membrane constriction (3) and membrane division (4).
Mentions: We have identified two genes, MDV1 and MDV2, that function with DNM1 to mediate mitochondrial fission. Our analysis of mdv1 and mdv2 cells, together with biochemical and ultrastructural analyses of the subcellular localization of Dnm1p, indicate that mitochondrial fission is a multi-step pathway, regulated by Mdv1p and Mdv2p, and similar in mechanism to dynamin-mediated endocytosis (Fig. 12; Otsuga et al. 1998; Schmid et al. 1998; Bleazard et al. 1999; Labrousse et al. 1999; Sesaki and Jensen 1999; Sever et al. 2000). These data support a model where Dnm1p is initially recruited from the cytosol to the mitochondrial outer membrane, where it subsequently assembles into punctate structures that ultimately mediate the division of mitochondrial membranes (Fig. 12, steps 1 and 2). Immunoelectron microscopy indicates that Dnm1p puncta are found at sites where the inner and outer mitochondrial membranes are coordinately constricted, and also on tubule tips that are presumably the end products of the division reaction (Bleazard et al. 1999). Because only a fraction of Dnm1p-containing structures are associated with constriction sites at steady state, it is probable that Dnm1p-mediated mitochondrial membrane constriction and/or mitochondrial membrane division are the rate-limiting steps in this pathway (Fig. 12, steps 3 and 4).

Bottom Line: Whereas localization of Mdv1p to these structures requires Dnm1p, localization of Mdv1p to mitochondrial membranes does not.Dnm1p-independent targeting of Mdv1p to mitochondria requires MDV2.Our data indicate that MDV2 also functions separately to regulate the assembly of Dnm1p into punctate structures.

View Article: PubMed Central - PubMed

Affiliation: Section of Molecular and Cellular Biology, University of California Davis, Davis, California 95616, USA.

ABSTRACT
Mitochondrial fission is mediated by the dynamin-related GTPase, Dnm1p, which assembles on the mitochondrial outer membrane into punctate structures associated with sites of membrane constriction and fission. We have identified additional nuclear genes required for mitochondrial fission, termed MDV (for mitochondrial division). MDV1 encodes a predicted soluble protein, containing a coiled-coil motif and seven COOH-terminal WD repeats. Genetic and two-hybrid analyses indicate that Mdv1p interacts with Dnm1p to mediate mitochondrial fission. In addition, Mdv1p colocalizes with Dnm1p in fission-mediating punctate structures on the mitochondrial outer membrane. Whereas localization of Mdv1p to these structures requires Dnm1p, localization of Mdv1p to mitochondrial membranes does not. This indicates that Mdv1p possesses a Dnm1p-independent mitochondrial targeting signal. Dnm1p-independent targeting of Mdv1p to mitochondria requires MDV2. Our data indicate that MDV2 also functions separately to regulate the assembly of Dnm1p into punctate structures. In contrast, Mdv1p is not required for the assembly of Dnm1p, but Dnm1p-containing punctate structures lacking Mdv1p are not able to complete division. Our studies suggest that mitochondrial fission is a multi-step process in which Mdv2p regulates the assembly of Dnm1p into punctate structures and together with Mdv1p functions later during fission to facilitate Dnm1p-dependent mitochondrial membrane constriction and/or division.

Show MeSH
Related in: MedlinePlus