DNAJC19, a mitochondrial cochaperone associated with cardiomyopathy, forms a complex with prohibitins to regulate cardiolipin remodeling

Ricarda Richter-Dennerlein; Anne Korwitz; Mathias Haag; Takashi Tatsuta; Sascha Dargazanli; Michael Baker; Thorsten Decker; Tobias Lamkemeyer; Elena I Rugarli; Thomas Langer

doi:10.1016/j.cmet.2014.04.016

DNAJC19, a mitochondrial cochaperone associated with cardiomyopathy, forms a complex with prohibitins to regulate cardiolipin remodeling

Cell Metab. 2014 Jul 1;20(1):158-71. doi: 10.1016/j.cmet.2014.04.016. Epub 2014 May 22.

Affiliations

¹ Institute for Genetics, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
² Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
³ Institute for Genetics, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
⁴ Institute for Genetics, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany; Max-Planck-Institute for Biology of Aging, 50931 Cologne, Germany. Electronic address: thomas.langer@uni-koeln.de.

PMID: 24856930
DOI: 10.1016/j.cmet.2014.04.016

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acyltransferases
Amino Acid Sequence
Animals
Cardiolipins / metabolism*
Cardiomyopathies / metabolism
Cardiomyopathies / pathology
Cell Line
HEK293 Cells
Humans
Membrane Transport Proteins / chemistry
Membrane Transport Proteins / metabolism
Metalloendopeptidases / metabolism
Mice
Mitochondria / metabolism*
Mitochondrial Membrane Transport Proteins / antagonists & inhibitors
Mitochondrial Membrane Transport Proteins / genetics
Mitochondrial Membrane Transport Proteins / metabolism*
Mitochondrial Membranes / metabolism
Mitochondrial Precursor Protein Import Complex Proteins
Molecular Sequence Data
Prohibitins
RNA Interference
RNA, Small Interfering / metabolism
Repressor Proteins / antagonists & inhibitors
Repressor Proteins / genetics
Repressor Proteins / metabolism
Saccharomyces cerevisiae / metabolism
Saccharomyces cerevisiae Proteins / chemistry
Saccharomyces cerevisiae Proteins / metabolism
Sequence Alignment
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Cardiolipins
DNAJC19 protein, human
Membrane Transport Proteins
Mitochondrial Membrane Transport Proteins
Mitochondrial Precursor Protein Import Complex Proteins
PAM18 J protein, S cerevisiae
PHB protein, human
PHB2 protein, human
Phb2 protein, mouse
Prohibitins
RNA, Small Interfering
Repressor Proteins
Saccharomyces cerevisiae Proteins
Transcription Factors
Acyltransferases
TAFAZZIN protein, human
Metalloendopeptidases
m-AAA proteases