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Mitochondrial stress protein actions during chemically induced renal proximal tubule cell death
1W. Alton Jones Cell Science Center, Lake Placid, NY 12946, USA.
Abstract:
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.
Insights
The nephrotoxicant tetrafluoroethyl-L-cysteine (TFEC) binds to mitochondrial dehydrogenase subunits, causing structural changes. This protein damage triggers the recognition of mitochondrial stress proteins like HSP60.
Area of Science:
- Biochemistry
- Toxicology
- Cell Biology
Background:
- The nephrotoxicant tetrafluoroethyl-L-cysteine (TFEC) covalently modifies mitochondrial proteins.
- These modified proteins are subunits of mitochondrial dehydrogenase multienzyme complexes crucial for cellular respiration.
Purpose of the Study:
- To investigate the consequences of TFEC-induced protein adduction in mitochondria.
- To identify the interactions between adducted dehydrogenase subunits and mitochondrial stress proteins.
Main Methods:
- Protein adduction analysis using TFEC.
- Identification of adducted mitochondrial proteins.
- Investigation of protein-protein interactions using mitochondrial stress proteins (HSP60, mortalin/PBP74).
Main Results:
- TFEC adduction specifically targets E2 and E3 subunits of alpha-ketoglutarate dehydrogenase.
- Adduction leads to the formation of tertiary complexes between adducted dehydrogenase subunits and HSP60/mortalin.
- Protein structural integrity is perturbed, enabling mitochondrial stress protein recognition.
Conclusions:
- TFEC-induced adduction disrupts mitochondrial protein structure and function.
- Mitochondrial stress proteins, particularly HSP60, are involved in recognizing and potentially maintaining the integrity of damaged proteins.
- These findings highlight a mechanism of cellular response to toxicant-induced mitochondrial damage in mammalian systems.