Transcriptional and cellular responses to defective mitochondrial proteolysis in fission yeast.
Lon and m-AAA are the principal, regulated proteases required for protein maturation and turnover in the mitochondrial matrix of diverse species. To understand their roles in fission yeast (Schizosaccharomyces pombe) mitochondria, we generated deletion strains lacking Lon and m-AAA, individually (Δl...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
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2011
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| _version_ | 1797054571400396800 |
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| author | Guha, S López-Maury, L Shaw, M Bähler, J Norbury, C Agashe, V |
| author_facet | Guha, S López-Maury, L Shaw, M Bähler, J Norbury, C Agashe, V |
| author_sort | Guha, S |
| collection | OXFORD |
| description | Lon and m-AAA are the principal, regulated proteases required for protein maturation and turnover in the mitochondrial matrix of diverse species. To understand their roles in fission yeast (Schizosaccharomyces pombe) mitochondria, we generated deletion strains lacking Lon and m-AAA, individually (Δlon1 and Δm-AAA) or together, Δlon1Δm-AAA (Δ/Δ). All three strains were viable but incapable of respiratory growth on a non-fermentable carbon source due to mitochondrial dysfunction. Confocal and electron microscopy revealed a decrease in membrane potential and ultrastructural changes in Δlon1, Δm-AAA and Δ/Δ mitochondria, consistent with a respiratory defect and aggregation of proteins in the mitochondrial matrix. To understand the global adaptations required for cell survival in the absence of Lon and m-AAA proteases, we compared genome-wide gene expression signatures of the deletion strains with the isogenic wild-type strain. Deletion of lon1 caused a distinctive transcriptional footprint of just 12 differentially expressed genes, 9 of which were up-regulated genes located on the proximal mitochondrial genome (mitochondrial DNA). In contrast, m-AAA deletion caused a much larger transcriptional response involving 268 almost exclusively nuclear genes. Genes ameliorating stress and iron assimilation were up-regulated, while diverse mitochondrial genes and other metabolic enzymes were down-regulated. The connection with iron dysregulation was further explored using biochemical, chemical and cellular assays. Although Δm-AAA and Δ/Δ contained more cellular iron than the wild-type strain, their transcriptomes strongly resembled a signature normally evoked by iron insufficiency or disrupted assembly of iron-sulfur clusters in mitochondria. Based on these findings, we posit that excess iron accumulation could contribute to the pathology of human neurodegenerative disorders arising from defects in m-AAA function. |
| first_indexed | 2024-03-06T18:59:05Z |
| format | Journal article |
| id | oxford-uuid:12e6dcbb-6b1a-4349-b152-e443ca1046ba |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:59:05Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:12e6dcbb-6b1a-4349-b152-e443ca1046ba2022-03-26T10:10:42ZTranscriptional and cellular responses to defective mitochondrial proteolysis in fission yeast.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:12e6dcbb-6b1a-4349-b152-e443ca1046baEnglishSymplectic Elements at Oxford2011Guha, SLópez-Maury, LShaw, MBähler, JNorbury, CAgashe, VLon and m-AAA are the principal, regulated proteases required for protein maturation and turnover in the mitochondrial matrix of diverse species. To understand their roles in fission yeast (Schizosaccharomyces pombe) mitochondria, we generated deletion strains lacking Lon and m-AAA, individually (Δlon1 and Δm-AAA) or together, Δlon1Δm-AAA (Δ/Δ). All three strains were viable but incapable of respiratory growth on a non-fermentable carbon source due to mitochondrial dysfunction. Confocal and electron microscopy revealed a decrease in membrane potential and ultrastructural changes in Δlon1, Δm-AAA and Δ/Δ mitochondria, consistent with a respiratory defect and aggregation of proteins in the mitochondrial matrix. To understand the global adaptations required for cell survival in the absence of Lon and m-AAA proteases, we compared genome-wide gene expression signatures of the deletion strains with the isogenic wild-type strain. Deletion of lon1 caused a distinctive transcriptional footprint of just 12 differentially expressed genes, 9 of which were up-regulated genes located on the proximal mitochondrial genome (mitochondrial DNA). In contrast, m-AAA deletion caused a much larger transcriptional response involving 268 almost exclusively nuclear genes. Genes ameliorating stress and iron assimilation were up-regulated, while diverse mitochondrial genes and other metabolic enzymes were down-regulated. The connection with iron dysregulation was further explored using biochemical, chemical and cellular assays. Although Δm-AAA and Δ/Δ contained more cellular iron than the wild-type strain, their transcriptomes strongly resembled a signature normally evoked by iron insufficiency or disrupted assembly of iron-sulfur clusters in mitochondria. Based on these findings, we posit that excess iron accumulation could contribute to the pathology of human neurodegenerative disorders arising from defects in m-AAA function. |
| spellingShingle | Guha, S López-Maury, L Shaw, M Bähler, J Norbury, C Agashe, V Transcriptional and cellular responses to defective mitochondrial proteolysis in fission yeast. |
| title | Transcriptional and cellular responses to defective mitochondrial proteolysis in fission yeast. |
| title_full | Transcriptional and cellular responses to defective mitochondrial proteolysis in fission yeast. |
| title_fullStr | Transcriptional and cellular responses to defective mitochondrial proteolysis in fission yeast. |
| title_full_unstemmed | Transcriptional and cellular responses to defective mitochondrial proteolysis in fission yeast. |
| title_short | Transcriptional and cellular responses to defective mitochondrial proteolysis in fission yeast. |
| title_sort | transcriptional and cellular responses to defective mitochondrial proteolysis in fission yeast |
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