Mitochondrial stress protein actions during chemically induced renal proximal tubule cell death.
We have previously shown that the potent mammalian nephrotoxicant tetrafluoroethyl-L-cysteine (TFEC) covalently modifies a select group of mitochondrial proteins prior to cell death. More recently we have identified these adducted proteins as subunits of mitochondrial dehydrogenase multienzyme complexes, which are involved in key regulatory steps of cellular respiration. Most importantly the E2 and E3 subunits of alpha-ketoglutarate dehydrogenase are adducted. We report here that the consequence of adduction is the formation of tertiary complexes between dehydrogenase subunits and the mitochondrial heat shock protein 60 (HSP60) and a HSP70 homolog (mortalin/PBP74). Thus, adduction perturbs protein structural integrity sufficiently to allow for mitochondrial stress protein recognition. These data also suggest that, in our mammalian system, HSP60 appears to act in the identification and maintenance of protein integrity, as has been previously established for simpler eukaryotic systems.
Bruschi
S A
SA
W. Alton Jones Cell Science Center, Lake Placid, NY 12946, USA.
Lindsay
J G
JG
D000818:Animals; D017209:Apoptosis; D018834:Chaperonin 60 / Q000378:metabolism*; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D011916:Rats, Inbred F344; D005466:Fluorocarbons
D018834:Chaperonin 60; D003545:Cysteine; D018840:HSP70 Heat-Shock Proteins; D006845:Hydrocarbons, Fluorinated; D007655:Ketoglutarate Dehydrogenase Complex; C064116:S-(1,1,2,2-tetrafluoroethyl)cysteine; D005466:Fluorocarbons