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A mitochondrial-focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria.

Hoppins S, Collins SR, Cassidy-Stone A, Hummel E, Devay RM, Lackner LL, Westermann B, Schuldiner M, Weissman JS, Nunnari J - J. Cell Biol. (2011)

Bottom Line: The MITO-MAP also reveals a large inner membrane-associated complex, which we term MitOS for mitochondrial organizing structure, comprised of Fcj1/Mitofilin, a conserved inner membrane protein, and five additional components.We show that MitOS acts in concert with ATP synthase dimers to organize the inner membrane and promote normal mitochondrial morphology.We propose that MitOS acts as a conserved mitochondrial skeletal structure that differentiates regions of the inner membrane to establish the normal internal architecture of mitochondria.

View Article: PubMed Central - HTML - PubMed

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

ABSTRACT
To broadly explore mitochondrial structure and function as well as the communication of mitochondria with other cellular pathways, we constructed a quantitative, high-density genetic interaction map (the MITO-MAP) in Saccharomyces cerevisiae. The MITO-MAP provides a comprehensive view of mitochondrial function including insights into the activity of uncharacterized mitochondrial proteins and the functional connection between mitochondria and the ER. The MITO-MAP also reveals a large inner membrane-associated complex, which we term MitOS for mitochondrial organizing structure, comprised of Fcj1/Mitofilin, a conserved inner membrane protein, and five additional components. MitOS physically and functionally interacts with both outer and inner membrane components and localizes to extended structures that wrap around the inner membrane. We show that MitOS acts in concert with ATP synthase dimers to organize the inner membrane and promote normal mitochondrial morphology. We propose that MitOS acts as a conserved mitochondrial skeletal structure that differentiates regions of the inner membrane to establish the normal internal architecture of mitochondria.

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Structure of genetic interactions within and between mitochondria and the secretory pathway. (A) A heat map of log10 P-values for the enrichment of synthetic genetic interactions (S-score < −3) between genes annotated as functioning in different pathways of the secretory system, mitochondria, or related pathways. Genes were manually assigned a single annotation based on curation of the literature (Table S2). Enrichment P-values were calculated using the binomial distribution as the probability of observing as many or more synthetic interactions between genes with the indicated annotations, given the number of measurements and an expected probability of synthetic interaction that accounts for the overall interaction frequency for each annotation (see Materials and methods for more details). Enrichment P-values were calculated after accounting for the overall frequency of interactions for each annotation. (B) A heat map of enrichments of synthetic interactions (as in A) for the different major branches of the cellular lipid biosynthesis machinery. (C) Genetic connection scatter plot for the average of ERMES component genes MDM10, MDM12, MDM34, and MMM1. The x axis represents the cosine correlation between the mean of ERMES genes interaction scores, and the y axis indicates the mean interaction score between the ERMES genes and each gene in the MITO-MAP. Every point in the scatter plot represents one gene. The cosine correlation values for points corresponding to the selected genes themselves were computed using the mean of the interaction score vectors for the remaining selected genes. In cases where the genetic interaction score was not measured, the point is plotted in gray along the line y = 0.
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fig2: Structure of genetic interactions within and between mitochondria and the secretory pathway. (A) A heat map of log10 P-values for the enrichment of synthetic genetic interactions (S-score < −3) between genes annotated as functioning in different pathways of the secretory system, mitochondria, or related pathways. Genes were manually assigned a single annotation based on curation of the literature (Table S2). Enrichment P-values were calculated using the binomial distribution as the probability of observing as many or more synthetic interactions between genes with the indicated annotations, given the number of measurements and an expected probability of synthetic interaction that accounts for the overall interaction frequency for each annotation (see Materials and methods for more details). Enrichment P-values were calculated after accounting for the overall frequency of interactions for each annotation. (B) A heat map of enrichments of synthetic interactions (as in A) for the different major branches of the cellular lipid biosynthesis machinery. (C) Genetic connection scatter plot for the average of ERMES component genes MDM10, MDM12, MDM34, and MMM1. The x axis represents the cosine correlation between the mean of ERMES genes interaction scores, and the y axis indicates the mean interaction score between the ERMES genes and each gene in the MITO-MAP. Every point in the scatter plot represents one gene. The cosine correlation values for points corresponding to the selected genes themselves were computed using the mean of the interaction score vectors for the remaining selected genes. In cases where the genetic interaction score was not measured, the point is plotted in gray along the line y = 0.

Mentions: Analysis of the MITO-MAP revealed a prominent modularity to organellar function (Fig. 2, A and B). Because of the high density of genes in the MITO-MAP coding for both mitochondrial and early secretory components, our map provides an unprecedented opportunity to explore the functional links between these two disparate but connected aspects of cell biology. There is a strong enrichment of genetic interaction between pairs of genes encoding proteins localized to either the ER or mitochondria (Fig. S2 A). In contrast, synthetic interactions between genes encoding ER and mitochondrial proteins are strongly de-enriched (Fig. S2 A). Furthermore, we explored the overall structure of interactions within and between these two systems by manually annotating the genes in the MITO-MAP according to published evidence supporting their role in particular pathways (Table S2), and computing whether synthetic interactions are enriched between genes pairs acting in each pair of pathways (Fig. 2 A). Enrichment of synthetic interactions between a pair of pathways indicates that mutations in one pathway make the cell increasingly reliant on proper functioning of the other pathway. In contrast, enrichment within a pathway indicates redundancy or parallel subpathways within an annotated pathway. Consistent with earlier studies (Schuldiner et al., 2005), there was considerable substructure to genes acting in the early secretory pathway. For example, protein folding, glycosylation, and trafficking genes showed enrichments for interactions with other components in the same or related pathways. The lipid biosynthetic pathways are of particular interest, as mitochondria and ER cooperate in phosphatidylethanolamine (PE) biosynthesis. Nonetheless, mitochondrial-specific lipid biosynthesis pathways interacted preferentially with mitochondrial localized functions (Fig. 2 B). Indeed, even PSD1, which encodes a mitochondrial-localized enzyme of the PE synthesis pathway, interacts predominantly with genes encoding mitochondrial proteins (Fig. S2 B). However, there are significant interactions between mitochondrial functions, sphingolipid metabolism, and lipid droplets, and, as expected, interactions between fatty acid biosynthesis and carbohydrate catabolism (Fig. 2 B).


A mitochondrial-focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria.

Hoppins S, Collins SR, Cassidy-Stone A, Hummel E, Devay RM, Lackner LL, Westermann B, Schuldiner M, Weissman JS, Nunnari J - J. Cell Biol. (2011)

Structure of genetic interactions within and between mitochondria and the secretory pathway. (A) A heat map of log10 P-values for the enrichment of synthetic genetic interactions (S-score < −3) between genes annotated as functioning in different pathways of the secretory system, mitochondria, or related pathways. Genes were manually assigned a single annotation based on curation of the literature (Table S2). Enrichment P-values were calculated using the binomial distribution as the probability of observing as many or more synthetic interactions between genes with the indicated annotations, given the number of measurements and an expected probability of synthetic interaction that accounts for the overall interaction frequency for each annotation (see Materials and methods for more details). Enrichment P-values were calculated after accounting for the overall frequency of interactions for each annotation. (B) A heat map of enrichments of synthetic interactions (as in A) for the different major branches of the cellular lipid biosynthesis machinery. (C) Genetic connection scatter plot for the average of ERMES component genes MDM10, MDM12, MDM34, and MMM1. The x axis represents the cosine correlation between the mean of ERMES genes interaction scores, and the y axis indicates the mean interaction score between the ERMES genes and each gene in the MITO-MAP. Every point in the scatter plot represents one gene. The cosine correlation values for points corresponding to the selected genes themselves were computed using the mean of the interaction score vectors for the remaining selected genes. In cases where the genetic interaction score was not measured, the point is plotted in gray along the line y = 0.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3198156&req=5

fig2: Structure of genetic interactions within and between mitochondria and the secretory pathway. (A) A heat map of log10 P-values for the enrichment of synthetic genetic interactions (S-score < −3) between genes annotated as functioning in different pathways of the secretory system, mitochondria, or related pathways. Genes were manually assigned a single annotation based on curation of the literature (Table S2). Enrichment P-values were calculated using the binomial distribution as the probability of observing as many or more synthetic interactions between genes with the indicated annotations, given the number of measurements and an expected probability of synthetic interaction that accounts for the overall interaction frequency for each annotation (see Materials and methods for more details). Enrichment P-values were calculated after accounting for the overall frequency of interactions for each annotation. (B) A heat map of enrichments of synthetic interactions (as in A) for the different major branches of the cellular lipid biosynthesis machinery. (C) Genetic connection scatter plot for the average of ERMES component genes MDM10, MDM12, MDM34, and MMM1. The x axis represents the cosine correlation between the mean of ERMES genes interaction scores, and the y axis indicates the mean interaction score between the ERMES genes and each gene in the MITO-MAP. Every point in the scatter plot represents one gene. The cosine correlation values for points corresponding to the selected genes themselves were computed using the mean of the interaction score vectors for the remaining selected genes. In cases where the genetic interaction score was not measured, the point is plotted in gray along the line y = 0.
Mentions: Analysis of the MITO-MAP revealed a prominent modularity to organellar function (Fig. 2, A and B). Because of the high density of genes in the MITO-MAP coding for both mitochondrial and early secretory components, our map provides an unprecedented opportunity to explore the functional links between these two disparate but connected aspects of cell biology. There is a strong enrichment of genetic interaction between pairs of genes encoding proteins localized to either the ER or mitochondria (Fig. S2 A). In contrast, synthetic interactions between genes encoding ER and mitochondrial proteins are strongly de-enriched (Fig. S2 A). Furthermore, we explored the overall structure of interactions within and between these two systems by manually annotating the genes in the MITO-MAP according to published evidence supporting their role in particular pathways (Table S2), and computing whether synthetic interactions are enriched between genes pairs acting in each pair of pathways (Fig. 2 A). Enrichment of synthetic interactions between a pair of pathways indicates that mutations in one pathway make the cell increasingly reliant on proper functioning of the other pathway. In contrast, enrichment within a pathway indicates redundancy or parallel subpathways within an annotated pathway. Consistent with earlier studies (Schuldiner et al., 2005), there was considerable substructure to genes acting in the early secretory pathway. For example, protein folding, glycosylation, and trafficking genes showed enrichments for interactions with other components in the same or related pathways. The lipid biosynthetic pathways are of particular interest, as mitochondria and ER cooperate in phosphatidylethanolamine (PE) biosynthesis. Nonetheless, mitochondrial-specific lipid biosynthesis pathways interacted preferentially with mitochondrial localized functions (Fig. 2 B). Indeed, even PSD1, which encodes a mitochondrial-localized enzyme of the PE synthesis pathway, interacts predominantly with genes encoding mitochondrial proteins (Fig. S2 B). However, there are significant interactions between mitochondrial functions, sphingolipid metabolism, and lipid droplets, and, as expected, interactions between fatty acid biosynthesis and carbohydrate catabolism (Fig. 2 B).

Bottom Line: The MITO-MAP also reveals a large inner membrane-associated complex, which we term MitOS for mitochondrial organizing structure, comprised of Fcj1/Mitofilin, a conserved inner membrane protein, and five additional components.We show that MitOS acts in concert with ATP synthase dimers to organize the inner membrane and promote normal mitochondrial morphology.We propose that MitOS acts as a conserved mitochondrial skeletal structure that differentiates regions of the inner membrane to establish the normal internal architecture of mitochondria.

View Article: PubMed Central - HTML - PubMed

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

ABSTRACT
To broadly explore mitochondrial structure and function as well as the communication of mitochondria with other cellular pathways, we constructed a quantitative, high-density genetic interaction map (the MITO-MAP) in Saccharomyces cerevisiae. The MITO-MAP provides a comprehensive view of mitochondrial function including insights into the activity of uncharacterized mitochondrial proteins and the functional connection between mitochondria and the ER. The MITO-MAP also reveals a large inner membrane-associated complex, which we term MitOS for mitochondrial organizing structure, comprised of Fcj1/Mitofilin, a conserved inner membrane protein, and five additional components. MitOS physically and functionally interacts with both outer and inner membrane components and localizes to extended structures that wrap around the inner membrane. We show that MitOS acts in concert with ATP synthase dimers to organize the inner membrane and promote normal mitochondrial morphology. We propose that MitOS acts as a conserved mitochondrial skeletal structure that differentiates regions of the inner membrane to establish the normal internal architecture of mitochondria.

Show MeSH
Related in: MedlinePlus