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A crucial role of mitochondrial Hsp40 in preventing dilated cardiomyopathy


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 α-subunit of DNA polymerase γ (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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Figure 1: Dnaja3 localizes to mitochondria and is differentially expressed during cardiac development and hypertrophy.
Figure 2: Dnaja3 deficiency leads to mitochondrial cardiomyopathy.
Figure 3: Enzymatic analysis of hearts from control and Dnaja3-cmKO mice.
Figure 4: Dnaja3 interacts with Polga and is essential for mtDNA replication.


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This work was supported by funds from the US National Cancer Institute (CA079871), Department of Defense BCRP (BC031105) and Boehringer Ingelheim Pharmaceuticals, Inc.

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Correspondence to Jiing-Dwan Lee.

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Supplementary information

Supplementary Fig. 1

Dnaja3 localizes to mitochondria during cardiac development and during pressure overload–induced hypertrophy. (PDF 387 kb)

Supplementary Fig. 2

Early cardiac development requires Dnaja3. (PDF 320 kb)

Supplementary Fig. 3

Increase apoptosis in cardiomyocytes lacking Dnaja3. (PDF 148 kb)

Supplementary Fig. 4

Mitochondrial defects in Dnaja3-deficient cardiomyocytes. (PDF 236 kb)

Supplementary Fig. 5

Mitochondrial fatty acid metabolism in Dnaja3-cmKO hearts. (PDF 172 kb)

Supplementary Fig. 6

Dnaja3 is not an immunoglobulin-binding protein. (PDF 44 kb)

Supplementary Methods (PDF 42 kb)

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Hayashi, M., Imanaka-Yoshida, K., Yoshida, T. et al. A crucial role of mitochondrial Hsp40 in preventing dilated cardiomyopathy. Nat Med 12, 128–132 (2006).

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