Mitochondrial morphological and functional defects in yeast caused by yme1 are suppressed by mutation of a 26S protease subunit homologue.

Campbell, Corey L.; Tanaka, Nobuhiro; White, Karen H.; Thorsness, Peter E.

doi:10.1091/mbc.5.8.899

Cited by 102 publications

(63 citation statements)

References 28 publications

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“…tants of the MPR1 gene, which encodes an essential regulatory subunit of the 26S proteasome, display pleiotropic defects including impaired growth on glycerol, aberrant mitochondria and overreplication of mtDNA (Rinaldi et al, 1998). Finally, mutation of the YNT1 gene, which encodes another regulatory proteasome subunit, suppresses mitochondrial morphology defects in mutants lacking Yme1, an ATP-dependent protease of the mitochondrial intermembrane space (Campbell et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Mdm30 Is an F-Box Protein Required for Maintenance of Fusion-competent Mitochondria in Yeast

Fritz

Weinbach

Westermann

2003

MBoC

127

150

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Mitochondrial fusion and fission play important roles for mitochondrial morphology and function. We identified Mdm30 as a novel component required for maintenance of fusion-competent mitochondria in yeast. The Mdm30 sequence contains an F-box motif that is commonly found in subunits of Skp1-Cdc53-F-box protein ubiquitin ligases. A fraction of Mdm30 is associated with mitochondria. Cells lacking Mdm30 contain highly aggregated or fragmented mitochondria instead of the branched tubular network seen in wild-type cells. ⌬mdm30 cells lose mitochondrial DNA at elevated temperature and fail to fuse mitochondria in zygotes at all temperatures. These defects are rescued by deletion of DNM1, a gene encoding a component of the mitochondrial division machinery. The protein level of Fzo1, a key component of the mitochondrial fusion machinery, is regulated by Mdm30. Elevated Fzo1 levels in cells lacking Mdm30 or in cells overexpressing Fzo1 from a heterologous promoter induce mitochondrial aggregation in a similar manner. Our results suggest that Mdm30 controls mitochondrial shape by regulating the steadystate level of Fzo1 and point to a connection of the ubiquitin/26S proteasome system and mitochondria. INTRODUCTIONMitochondria are highly dynamic organelles. In many eukaryotic cell types they continuously move along cytoskeletal tracks and frequently fuse and divide. Their shape varies depending on the cell type, physiological status, and nutritional conditions (Bereiter-Hahn and Vö th, 1994;Yaffe, 1999;Griparic and van der Bliek, 2001;Westermann, 2002). Recent studies have shown that mitochondrial dynamics is crucial for a variety of cellular functions. For example, fusion of mitochondria is important for sperm development in Drosophila (Hales and Fuller, 1997) and for maintenance of mitochondrial DNA (mtDNA) in yeast (Berger and Yaffe, 2000). Furthermore, fusion is required for the formation of intracellular mitochondrial networks that allow the dissipation of energy in the cell (Skulachev, 2001) and for complementation of mitochondrial gene products, a mechanism thought to constitute a defense against cellular aging (Ono et al., 2001). Mitochondrial fission is an important step in apoptosis (Frank et al., 2001) and is required for embryonic development in nematodes (Labrousse et al., 1999). Several of the proteins determining mitochondrial behavior have been identified in recent years Yaffe, 1999;Jensen et al., 2000;Boldogh et al., 2001;Shaw and Nunnari, 2002;Westermann and Prokisch, 2002). Yet, many of the molecular processes regulating mitochondrial dynamics remain to be described.The molecular components of mitochondrial fusion and fission have been most extensively studied in budding yeast. Yeast mitochondria form an extended tubular network located below the cell cortex (Hoffmann and Avers, 1973). Mitochondria undergo gross structural changes during adaptation to nutritional conditions and growth phase (Stevens, 1981;Pon and Schatz, 1991;Egner et al., 2002). During vegetative growth, the continuity of the mitochondr...

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Section: Discussionmentioning

confidence: 99%

Mdm30 Is an F-Box Protein Required for Maintenance of Fusion-competent Mitochondria in Yeast

Fritz

Weinbach

Westermann

2003

MBoC

127

150

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“…Recently two genes, RCA1 and AFG3, were shown to control the assembly of more than one respiratory complex [21]. These genes belong to the AAA protein family and would code for ATP-dependent metallo-proteases required for the degradation of incompletely synthesized or misfolded polypeptides of the mitochondrial inner membrane [22][23][24][25][26][27][28]. The inactivation of RCAI or AFG3 was shown to diminish the NADH cytochrome c oxido-reductase, the cytochrome c oxidase and the ATPase activities, as well as to cause an arrest in assembly of the complexes IlI and IV and to delay the assembly of the F1-ATPase complex components [21,29].…”

Section: Discussionmentioning

confidence: 99%

The Saccharomyces cerevisiae OXA1 gene is required for the correct assembly of cytochrome c oxidase and oligomycin‐sensitive ATP synthase

et al. 1996

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The nuclear gene OXAI was first isolated in Saccharomyces cevevisiae and found to be required a~ a posttranslational step in cytochrome c oxidase biogenesis, probably at the level of assembly. Mutations in OXAI lead to a complete respiratory deficiency. The protein Oxalp is conserved through evolution and a human homolog has been Isolated by functional complementatlon of a yeast oxal-mutant. In order to further our understanding of the role of Oxalp, we have constructed two yeast strains in which the OXAI open reading frame was almost totally deleted. Cytochrome spectra and enzymatic activity measurements show the absence of heine as3 and of a cytochrome e oxido-reductase activity and dramatic decrease of the oligomycin sensitive ATPase activity. Analysis of the respiratory complexes in non-denaturing gels reveals that Oxalp is necessary for the correct assembly of the cytochrome c oxidase and the ATP synthase complex.

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“…These include an increased rate of escape of DNA from mitochondria and its subsequent capture by the nucleus, an inability to grow on nonfermentable carbon sources at 370, and extremely slow growth when cells contain both a ymel nuclear mutation and large deletions of the mitochondrial genome. In addition, cells harboring a mutation in YME1 contain punctate and grossly swollen mitochondria instead of the normal reticulated network of mitochondrial compartments (Campbell et al, 1994). YME1 encodes a protein, Ymelp, that is localized to mitochondria, has a molecular mass of 82 kDa, and contains two conserved sequence elements; the first is implicated in the binding and hydrolysis of ATP, and the second is homologous to the active site residues of * Corresponding author.…”

Section: Introductionmentioning

confidence: 99%

“…YME1 encodes a protein, Ymelp, that is localized to mitochondria, has a molecular mass of 82 kDa, and contains two conserved sequence elements; the first is implicated in the binding and hydrolysis of ATP, and the second is homologous to the active site residues of * Corresponding author. neutral, zinc-dependent protease Campbell et al, 1994). Ymelp is closely related to the Escherichia coli protein FtsH, which was identified in a screen for cell division mutants (Tomoyasu et al, 1993b).…”

Section: Introductionmentioning

confidence: 99%

“…Secl8p is required for membrane fusion events in the secretory pathway (Eakle et al, 1988;Wilson et al, 1989) and Paslp is involved in peroxisome biogenesis (Erdmann et al, 1991). Finally, Ymelp is homologous to Yntlp, which was isolated as a bypass suppressor of a YME1 deletion (Campbell et al, 1994). An altered form of Yntlp, which is homologous to a subunit of the 26S proteosome, can partially compensate for the absence of Ymelp.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Biochemical and functional analysis of the YME1 gene product, an ATP and zinc-dependent mitochondrial protease from S. cerevisiae.

Weber

Hanekamp

Thorsness

1996

MBoC

Self Cite

129

106

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Inactivation of YME1 in yeast causes several distinct phenotypes: an increased rate of DNA escape from mitochondria, temperature-sensitive growth on nonfermentable carbon sources, extremely slow growth when mitochondrial DNA is completely absent from the cell, and altered morphology of the mitochondrial compartment. The protein encoded by YME1, Ymelp, contains two highly conserved sequence elements, one implicated in the binding and hydrolysis of ATP, and the second characteristic of active site residues found in neutral, zinc-dependent proteases. Both the putative ATPase and zinc-dependent protease elements are necessary for the function of Ymelp as genes having mutations in critical residues of either of these motifs are unable to suppress any of the phenotypes exhibited by ymel deletion strains. Ymelp co-fractionates with proteins associated with the mitochondrial inner membrane, is tightly associated with this membrane, and is oriented with the bulk of the protein facing the matrix. Unassembled subunit II of cytochrome oxidase is stabilized in ymel yeast strains. The data support a model in which Ymelp is an ATP and zinc-dependent protease associated with the matrix side of the inner mitochondrial membrane. Subunit II of cytochrome oxidase, when not assembled into a higher order complex, is a likely substrate of Ymelp.

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Mitochondrial morphological and functional defects in yeast caused by yme1 are suppressed by mutation of a 26S protease subunit homologue.

Cited by 102 publications

References 28 publications

Mdm30 Is an F-Box Protein Required for Maintenance of Fusion-competent Mitochondria in Yeast

Mdm30 Is an F-Box Protein Required for Maintenance of Fusion-competent Mitochondria in Yeast

The Saccharomyces cerevisiae OXA1 gene is required for the correct assembly of cytochrome c oxidase and oligomycin‐sensitive ATP synthase

Biochemical and functional analysis of the YME1 gene product, an ATP and zinc-dependent mitochondrial protease from S. cerevisiae.

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