A Genomewide Screen for Petite-negative Yeast Strains Yields a New Subunit of the i-AAA Protease Complex

Dunn, Cory D.; Lee, Marina S.; Spencer, Forrest; Jensen, Robert E.

doi:10.1091/mbc.e05-06-0585

Cited by 71 publications

(102 citation statements)

References 86 publications

(115 reference statements)

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“…It has been previously reported that S. cerevisiae does not tolerate loss of mtDNA combined with activation of the cAMP-PKA pathway by IRA2 or PDE2 deletion (Dunn et al 2006). Our analysis demonstrates that activation of the pathway by BCY1 deletion is tolerated in rich growth media, but not under starvation conditions with additional stress.…”

Section: (D-g) Error Bars Indicate Standard Deviations Of Three Indepsupporting

confidence: 47%

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Dysfunctional Mitochondria Modulate cAMP-PKA Signaling and Filamentous and Invasive Growth of Saccharomyces cerevisiae

Aun¹,

Tamm²,

Sedman

2013

Genetics

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Mitochondrial metabolism is targeted by conserved signaling pathways that mediate external information to the cell. However, less is known about whether mitochondrial dysfunction interferes with signaling and thereby modulates the cellular response to environmental changes. In this study, we analyzed defective filamentous and invasive growth of the yeast Saccharomyces cerevisiae strains that have a dysfunctional mitochondrial genome (rho mutants). We found that the morphogenetic defect of rho mutants was caused by specific downregulation of FLO11, the adhesin essential for invasive and filamentous growth, and did not result from general metabolic changes brought about by interorganellar retrograde signaling. Transcription of FLO11 is known to be regulated by several signaling pathways, including the filamentous-growth-specific MAPK and cAMP-activated protein kinase A (cAMP-PKA) pathways. Our analysis showed that the filamentous-growth-specific MAPK pathway retained functionality in respiratory-deficient yeast cells. In contrast, the cAMP-PKA pathway was downregulated, explaining also various phenotypic traits observed in rho mutants. Thus, our results indicate that dysfunctional mitochondria modulate the output of the conserved cAMP-PKA signaling pathway.

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Section: (D-g) Error Bars Indicate Standard Deviations Of Three Indepsupporting

confidence: 47%

“…It has been reported that ira2D and pde2D mutants do not tolerate the loss of mtDNA (Dunn et al 2006). This suggests that the hyperactivation of Ras2 or the elevated levels of cAMP are not tolerated in respiratory-deficient strains.…”

Section: Discussionmentioning

confidence: 99%

Dysfunctional Mitochondria Modulate cAMP-PKA Signaling and Filamentous and Invasive Growth of Saccharomyces cerevisiae

Aun¹,

Tamm²,

Sedman

2013

Genetics

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“…The highest-scoring predicted difference between CAB115/1-2 and its parent strain CAB115 was in a previously identified (Dunn et al 2006) gene, MGR1. Sequence analysis of MGR1 revealed a G-to-T transversion at nucleotide 778, resulting in a premature stop at codon 261 (of 417), termed mgr1-1.…”

Section: Resultsmentioning

confidence: 99%

“…The Mgr1 and Mgr3 proteins have recently been shown to associate with each other and with Yme1 (Dunn et al 2006(Dunn et al , 2008, the inner mitochondrial membrane AAA ATP-dependent zinc protease (Nakai et al 1995;Pearce and Sherman 1995;Weber et al 1996) facing the intermembrane space (Leonhard et al 1996). These newly discovered subunits of the i-AAA complex bind to known Yme1 substrates and are required for normal degradation rates in vivo, suggesting that they recruit substrate proteins to Yme1 for degradation (Dunn et al 2008).…”

Section: Resultsmentioning

confidence: 99%

“…The genetic analysis described above demonstrated that the absence of Mgr1 and/or Mgr3 proteins allows overproduced Oxa1 to partially compensate for the lack of Cox18 in the assembly of cytochrome c oxidase. Since mgr1 and mgr3 mutations appear to decrease proteolysis by Yme1 (Dunn et al 2006(Dunn et al , 2008, we asked whether a yme1 deletion might also allow respiratory growth in the cox18D [OXA1] background. Interestingly, the yme1D cox18D [OXA1] strain failed to grow on nonfermentable carbon sources ( Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

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Translocation and Assembly of Mitochondrially Coded Saccharomyces cerevisiae Cytochrome c Oxidase Subunit Cox2 by Oxa1 and Yme1 in the Absence of Cox18

et al. 2009

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Members of the Oxa1/YidC/Alb3 family of protein translocases are essential for assembly of energytransducing membrane complexes. In Saccharomyces cerevisiae, Oxa1 and its paralog, Cox18, are required for assembly of Cox2, a mitochondrially encoded subunit of cytochrome c oxidase. Oxa1 is known to be required for cotranslational export of the Cox2 N-terminal domain across the inner mitochondrial membrane, while Cox18 is known to be required for post-translational export of the Cox2 C-tail domain. We find that overexpression of Oxa1 does not compensate for the absence of Cox18 at the level of respiratory growth. However, it does promote some translocation of the Cox2 C-tail domain across the inner membrane and causes increased accumulation of Cox2, which remains unassembled. This result suggests that Cox18 not only translocates the C-tail, but also must deliver it in a distinct state competent for cytochrome oxidase assembly. We identified respiring mutants from a cox18D strain overexpressing OXA1, whose respiratory growth requires overexpression of OXA1. The recessive nuclear mutations allow some assembly of Cox2 into cytochrome c oxidase. After failing to identify these mutations by methods based on transformation, we successfully located them to MGR1 and MGR3 by comparative hybridization to whole-genome tiling arrays and microarray-assisted bulk segregant analysis followed by linkage mapping. While Mgr1 and Mgr3 are known to associate with the Yme1 mitochondrial inner membrane i-AAA protease and to participate in membrane protein degradation, their absence does not appear to stabilize Cox2 under these conditions. Instead, Yme1 probably chaperones the folding and/or assembly of Oxa1-exported Cox2 in the absence of Mrg1 or Mgr3, since respiratory growth and cytochrome c oxidase assembly in a cox18 mgr3 double-mutant strain overexpressing OXA1 is YME1 dependent.

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mPOS is a novel mitochondrial trigger of cell death – implications for neurodegeneration

Coyne

Chen

2017

FEBS Letters

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In addition to its central role in energy metabolism, the mitochondrion has many other functions essential for cell survival. When stressed, the multifunctional mitochondria are expected to engender multifaceted cell stress with complex physiological consequences. Potential extra-mitochondrial proteostatic burdens imposed by inefficient protein import have been largely overlooked. Accumulating evidence suggests that a diverse range of pathogenic mitochondrial stressors, which do not directly target the core protein import machinery, can reduce cell fitness by disrupting the proteostatic network in the cytosol. The resulting stress, named mitochondrial precursor overaccumulation stress (mPOS), is characterized by the toxic accumulation of unimported mitochondrial proteins in the cytosol. Here, we review our current understanding of how mitochondrial dysfunction can impact the cytosolic proteome and proteostatic signaling. We also discuss the intriguing possibility that the mPOS model may help untangle the cause-effect relationship between mitochondrial dysfunction and cytosolic protein aggregation, which are probably the two most prominent molecular hallmarks of neurodegenerative disease.

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A Genomewide Screen for Petite-negative Yeast Strains Yields a New Subunit of the i-AAA Protease Complex

Cited by 71 publications

References 86 publications

Dysfunctional Mitochondria Modulate cAMP-PKA Signaling and Filamentous and Invasive Growth of Saccharomyces cerevisiae

Dysfunctional Mitochondria Modulate cAMP-PKA Signaling and Filamentous and Invasive Growth of Saccharomyces cerevisiae

Translocation and Assembly of Mitochondrially Coded Saccharomyces cerevisiae Cytochrome c Oxidase Subunit Cox2 by Oxa1 and Yme1 in the Absence of Cox18

mPOS is a novel mitochondrial trigger of cell death – implications for neurodegeneration

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