Cell Stress and Chaperones

, Volume 17, Issue 1, pp 57–66 | Cite as

Reactivation of protein aggregates by mortalin and Tid1—the human mitochondrial Hsp70 chaperone system

  • Ohad Iosefson
  • Shelly Sharon
  • Pierre Goloubinoff
  • Abdussalam Azem
Original Paper


The mitochondrial 70-kDa heat shock protein (mtHsp70), also known in humans as mortalin, is a central component of the mitochondrial protein import motor and plays a key role in the folding of matrix-localized mitochondrial proteins. MtHsp70 is assisted by a member of the 40-kDa heat shock protein co-chaperone family named Tid1 and a nucleotide exchange factor. Whereas, yeast mtHsp70 has been extensively studied in the context of protein import in the mitochondria, and the bacterial 70-kDa heat shock protein was recently shown to act as an ATP-fuelled unfolding enzyme capable of detoxifying stably misfolded polypeptides into harmless natively refolded proteins, little is known about the molecular functions of the human mortalin in protein homeostasis. Here, we developed novel and efficient purification protocols for mortalin and the two spliced versions of Tid1, Tid1-S, and Tid1-L and showed that mortalin can mediate the in vitro ATP-dependent reactivation of stable-preformed heat-denatured model aggregates, with the assistance of Mge1 and either Tid1-L or Tid1-S co-chaperones or yeast Mdj1. Thus, in addition of being a central component of the protein import machinery, human mortalin together with Tid1, may serve as a protein disaggregating machine which, for lack of Hsp100/ClpB disaggregating co-chaperones, may carry alone the scavenging of toxic protein aggregates in stressed, diseased, or aging human mitochondria.


Mitochondrial Hsp70 Tid1 Hep1 Ssc1 Disaggregation 



We thank Zvi Fishelson and Moran Saar for plasmids of mortalin’s domains. A.A. is supported by the German-Israeli Foundation for Scientific Research and Development (GIF-1012/08) and Israel Science Foundation (452/09). O.I. was partially supported by a grant from Philip Morris International.

Supplementary material

12192_2011_285_MOESM1_ESM.doc (842 kb)
Supplementary Fig. 1 Sequence alignment of human mortalin with yeast mtHsp70s (Ssc1, Ssq1, and Ecm10) and E. coli DnaK. (DOC 842 kb)
12192_2011_285_MOESM2_ESM.doc (530 kb)
Supplementary Fig. 2 Sequence alignment of human Tid1-L and Tid1-S, yeast mtHsp40 (Mdj1). and E coli DnaJ. (DOC 530 kb)
12192_2011_285_MOESM3_ESM.doc (1.2 mb)
Supplementary Fig. 3 Purification steps of mortalin. (DOC 1,255 kb)
12192_2011_285_MOESM4_ESM.doc (1.4 mb)
Supplementary Fig. 4 Purification steps of Tid1-L. (DOC 1,388 kb)
12192_2011_285_MOESM5_ESM.doc (52 kb)
Supplementary Fig. 5 The ATPase activity of mortalin is not stimulated by Tid1-L H121Q, under single-turnover conditions. (DOC 52 kb)
12192_2011_285_MOESM6_ESM.doc (56 kb)
Supplementary Fig. 6 Time-dependent reactivation of stable G6PDH aggregates by mortalin and mortalin-V482F. (DOC 56 kb)
12192_2011_285_MOESM7_ESM.doc (36 kb)
Supplementary Table 1 Sequence of primers (DOC 36 kb)


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Copyright information

© Cell Stress Society International 2011

Authors and Affiliations

  • Ohad Iosefson
    • 1
  • Shelly Sharon
    • 1
  • Pierre Goloubinoff
    • 2
  • Abdussalam Azem
    • 1
  1. 1.Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life SciencesTel Aviv UniversityTel AvivIsrael
  2. 2.Département de Biologie Moléculaire VégétaleUniversité de LausanneLausanneSwitzerland

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