Nature Medicine
- 12, 128 - 132 (2005)
Published online: 4 December 2005; | doi:10.1038/nm1327
A crucial role of mitochondrial Hsp40 in preventing dilated cardiomyopathyMasaaki Hayashi1, Kyoko Imanaka-Yoshida2, Toshimichi Yoshida2, Malcolm Wood1, Colleen Fearns1, Revati J Tatake3 & Jiing-Dwan Lee11
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037-1000, USA. 2
Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. 3
Boehringer Ingelheim Pharmaceuticals, Inc., Research and Development Center, 900 Ridgebury Road, Ridgefield, Connecticut 06877-1058, USA.
Correspondence should be addressed to Jiing-Dwan Lee jdlee@scripps.edu Many heat-shock proteins (Hsp) are members of evolutionarily conserved families of chaperone proteins that inhibit the aggregation of unfolded polypeptides and refold denatured proteins, thereby remedying phenotypic effects that may result from protein aggregation or protein instability1,
2. Here we report that the mitochondrial chaperone Hsp40, also known as Dnaja3 or Tid1, is differentially expressed during cardiac development and pathological hypertrophy. Mice deficient in Dnaja3 developed dilated cardiomyopathy (DCM) and died before 10 weeks of age. Progressive respiratory chain deficiency and decreased copy number of mitochondrial DNA were evident in cardiomyocytes lacking Dnaja3. Profiling of Dnaja3-interacting proteins identified the  -subunit of DNA polymerase  (Polga) as a client protein. These findings suggest that Dnaja3 is crucial for mitochondrial biogenesis, at least in part, through its chaperone activity on Polga and provide genetic evidence of the necessity for mitochondrial Hsp40 in preventing DCM.
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