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PMID:27402848

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Citation

Yadav, PK and Rajasekharan, R (2016) Misregulation of a DDHD Domain-containing Lipase Causes Mitochondrial Dysfunction in Yeast. J. Biol. Chem. 291:18562-81

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.

Links

PubMed PMC5000100 Online version:10.1074/jbc.M116.733378

Keywords


Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

YEAST:AFT1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(SGD:S000005548)

Seeded From UniProt

complete

YEAST:AFT1

involved_in

GO:0032048: cardiolipin metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:AFT1

enables

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

YEAST:CRD1

involved_in

GO:0006644: phospholipid metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:AFT2

involved_in

GO:0032048: cardiolipin metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:AFT2

enables

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

YEAST:AFT2

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(SGD:S000005548)

Seeded From UniProt

complete

YEAST:YOR22

enables

GO:0004620: phospholipase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(CHEBI:28494)|has_input:(CHEBI:16038)|has_input:(CHEBI:17517)

Seeded From UniProt

complete

YEAST:YOR22

involved_in

GO:0006644: phospholipid metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:YOR22

involved_in

GO:0032048: cardiolipin metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:YOR22

involved_in

GO:0046337: phosphatidylethanolamine metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

YEAST:YOR22

enables

GO:0004620: phospholipase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

YEAST:YOR22

enables

GO:0004620: phospholipase activity

ECO:0000314: direct assay evidence used in manual assertion

F

has_direct_input:(CHEBI:28494)|has_direct_input:(CHEBI:16038)|has_direct_input:(CHEBI:17517)

Seeded From UniProt

complete

Notes

See also

References

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