Mutations in the sHSPs HSPB1 (Hsp27) and HSPB8 (Hsp22) cause axonal Charcot–Marie–Tooth (CMT) disease and related disorders 27, 28, 29, 30, 31, 32, 33. sHSPs maintain cellular proteostasis through rapidly recognizing unfolded or misfolded proteins and transferring them to larger ATP-dependent chaperones 24, 25, 26. The monomeric low molecular mass (12–45 kDa) subunits are the building blocks for dynamic oligomeric ensembles up to 600 kDa and larger 23, 24. Like bacteria, humans also possess a class of ATP-independent chaperones known as small heat shock proteins (sHSPs). The periplasm is devoid of ATP and contains several ATP-independent chaperones such as Skp, Spy and SurA 21, 22. The periplasm of Gram-negative bacteria is considered the equivalent of the mitochondrial IMS and forms an excellent example of a multi-chaperone system. However, most cellular compartments harbour multiple chaperones that cooperate to counter protein aggregation, and chaperones that complement Skd3/ClpB in the mitochondrial IMS have yet to be identified. Skd3/ClpB is the only IMS chaperone known to counter protein aggregation after substrate import 20. The small TIMMs and Mia40/CHCHD4 protect, respectively, transmembrane and disulphide-rich proteins during mitochondrial import 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19. The only IMS chaperones known so far are the small translocases of the inner mitochondrial membrane (TIMMs), CHCHD4 (Mia40 in yeast) and ClpB (Skd3 in yeast). However, classical chaperones, like the Hsp70 and Hsp90 families, were not found in the mitochondrial intermembrane space (IMS) 7. The mitochondrial matrix is equipped with multiple chaperone systems, including mHSP60 and mHSP70 (refs. Most mitochondrial proteins are therefore imported from the cytosol, and this poses a considerable burden on mitochondrial surveillance systems 4, 5. Mitochondria are composed of more than 1,100 proteins, of which the nuclear genome encodes more than 99% (refs. Our results reveal that small heat shock proteins form a chaperone system that operates in the mitochondrial intermembrane space. Charcot–Marie–Tooth disease-causing mutations disturb the mitochondrial function of HSPB1, potentially linking previously observed mitochondrial dysfunction in Charcot–Marie–Tooth type 2F to its role in the mitochondrial intermembrane space. Depletion of small heat shock proteins leads to mitochondrial swelling and reduced respiration, while aggregation of aggregation-prone substrates is countered in their presence. Protein misfolding in the mitochondrial intermembrane space leads to increased recruitment of small heat shock proteins. Here we show that cytosolic small heat shock proteins are imported under basal conditions into the mitochondrial intermembrane space, where they operate as molecular chaperones. While chaperones of the mitochondrial matrix are well characterized, it is poorly understood which chaperones protect the mitochondrial intermembrane space. Mitochondria are complex organelles with different compartments, each harbouring their own protein quality control factors.
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