MOLECULAR CHAPERONES COOPERATE WITH PIM1 PROTEASE IN THE DEGRADATION OF MISFOLDED PROTEINS IN MITOCHONDRIA

ATP dependent proteolytic degradation of misfolded proteins in the mit ochondrial matrix is mediated by the PIM1 protease and depends on the molecular chaperone proteins mt-hsp70 and Mdj1p. Chaperone function is essential to maintain misfolded proteins in a soluble state, a prereq uisite for their degradation by PIM1 protease. In the absence of funct ional mt-hsp70 or Mdj1p misfolded proteins either remain associated wi th mt-hsp70 or form aggregates and thereby are no longer substrates fo r PIM1 protease. Mdj1p is shown to regulate the ATP dependent associat ion of an unfolded polypeptide chain,vith mt-hsp70 affecting binding t o as well as release from mt-hsp70. These findings establish a central role of molecular chaperone proteins in the degradation of misfolded proteins by PIM1 protease and thereby demonstrate a functional interre lation between components of the folding machinery and the proteolytic system within mitochondria.