title: Misregulation of a DDHD Domain-containing Lipase Causes Mitochondrial Dysfunction in Yeast.
abstract: The DDHD domain-containing proteins, which belong to the intracellular phospholipase A1 (iPLA1) family, have been predicted to be involved in phospholipid metabolism, lipid trafficking, membrane turnover, and signaling. Defective cardiolipin (CL), phosphatidylethanolamine, and phosphatidylglycerol remodeling cause Barth syndrome and mitochondrial dysfunction. Here, we report that Yor022c is a Ddl1 (DDHD domain-containing lipase 1) that hydrolyzes CL, phosphatidylethanolamine, and phosphatidylglycerol. Ddl1 has been implicated in the remodeling of mitochondrial phospholipids and CL degradation. Our data also suggested that the accumulation of monolysocardiolipin is deleterious to the cells. We show that Aft1 and Aft2 transcription factors antagonistically regulate the DDL1 gene. This study reveals that the misregulation of DDL1 by Aft1/2 transcription factors alters CL metabolism and causes mitochondrial dysfunction in the cells. In humans, mutations in the DDHD1 and DDHD2 genes cause specific types of hereditary spastic paraplegia (SPG28 and SPG54, respectively), and the yeast DDL1-defective strain produces similar phenotypes of hereditary spastic paraplegia (mitochondrial dysfunction and defects in lipid metabolism). Therefore, the DDL1-defective strain could be a good model system for understanding hereditary spastic paraplegia.
authors.affiliation: From the Lipidomic Centre, Department of Lipid Science and the Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research (CSIR)-Central Food Technological Research Institute (CFTRI), Mysore 570020, Karnataka, India.
authors.forename: Pradeep Kumar
authors.initials: PK
authors.lastname: Yadav
authors.affiliation: From the Lipidomic Centre, Department of Lipid Science and the Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research (CSIR)-Central Food Technological Research Institute (CFTRI), Mysore 570020, Karnataka, India ram@cftri.com.
authors.forename: Ram
authors.identifier: 0000-0002-2124-6013
authors.initials: R
authors.lastname: Rajasekharan
mesh_terms: D015971:Gene Expression Regulation, Enzymologic; D015966:Gene Expression Regulation, Fungal; D008049:Lipase / Q000096:biosynthesis* / Q000235:genetics; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C090297:AFT1 protein, S cerevisiae; C436328:Aft2 protein, S cerevisiae; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D008049:Lipase
keywords: AFT1/2 transcription factors; Barth syndrome; DDHD domain; YOR022C; cardiolipin; gene regulation; hereditary spastic paraplegia; metabolism; mitochondria; phospholipid