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Free keywords:
Amino Acid Sequence
Animals
Cardiolipins/*metabolism
Cardiomyopathies/metabolism/pathology
Cell Line
HEK293 Cells
Humans
Membrane Transport Proteins/chemistry/metabolism
Metalloendopeptidases/metabolism
Mice
Mitochondria/*metabolism
Mitochondrial Membrane Transport Proteins/antagonists &
inhibitors/genetics/*metabolism
Mitochondrial Membranes/metabolism
Molecular Sequence Data
RNA Interference
RNA, Small Interfering/metabolism
Repressor Proteins/antagonists & inhibitors/genetics/metabolism
Saccharomyces cerevisiae/metabolism
Saccharomyces cerevisiae Proteins/chemistry/metabolism
Sequence Alignment
Transcription Factors/antagonists & inhibitors/genetics/metabolism
Abstract:
Prohibitins form large protein and lipid scaffolds in the inner membrane of mitochondria that are required for mitochondrial morphogenesis, neuronal survival, and normal lifespan. Here, we have defined the interactome of PHB2 in mitochondria and identified DNAJC19, mutated in dilated cardiomyopathy with ataxia, as binding partner of PHB complexes. We observed impaired cell growth, defective cristae morphogenesis, and similar transcriptional responses in the absence of either DNAJC19 or PHB2. The loss of PHB/DNAJC19 complexes affects cardiolipin acylation and leads to the accumulation of cardiolipin species with altered acyl chains. Similar defects occur in cells lacking the transacylase tafazzin, which is mutated in Barth syndrome. Our experiments suggest that PHB/DNAJC19 membrane domains regulate cardiolipin remodeling by tafazzin and explain similar clinical symptoms in two inherited cardiomyopathies by an impaired cardiolipin metabolism in mitochondrial membranes.
