Misregulation of a DDHD Domain-containing Lipase Causes Mitochondrial Dysfunction in Yeast.

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 domaincontaining
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.Weshow 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
theDDHD1andDDHD2genes 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.