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Inhibition of ERK Activation Promotes Recovery of Mitochondrial Function Following Injury in Renal Cells
Author(s) -
Nowak Grazyna
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1137-d
Subject(s) - mitochondrion , mapk/erk pathway , chemistry , apoptosis , respiration , cytochrome c oxidase , electron transport chain , respiratory chain , microbiology and biotechnology , pharmacology , biochemistry , biology , signal transduction , anatomy
Previously, we have shown that activation of ERK by oxidant ( tert ‐butylhydroperoxide, TBHP) exposure is involved in mitochondrial dysfunction in renal proximal tubular cells (RPTC). This study examined whether inhibition of ERK activation protects against oxidant‐induced mitochondrial dysfunction or promotes recovery of mitochondrial functions following injury. Primary cultures of RPTC were exposed to TBHP (0.3 mM) and mitochondrial respiratory functions were examined at the end of TBHP exposure and at 1, 2, and 4 hours following the exposure. Basal respiration decreased 41% at the end of TBHP exposure and remained decreased for 4 hr. Electron transport rate decreased 69% in injured RPTC and did not improve during 4 hr after TBHP exposure. Complex I (NADH:Ubiquinone Oxidoreductase)‐linked state 3 respiration was reduced 35% by TBHP and remained at this level for 4 hr. In contrast, complex II (Succinate:Ubiquinone Oxidoreductase)‐ and complex IV (Cytochrome Oxidase)‐linked state 3 respirations were unchanged. These changes were preceded by a rapid (within 10 min of TBHP exposure) activation of ERK in RPTC and mitochondria that persisted for 8 hr. Inhibition of ERK activation using U0126 (MEK inhibitor; 10 μM) did not alter TBHP‐induced decreases in electron transport rate and state 3 respiration, but resulted in a gradual restoration of these functions within 4 hr following injury. Thus, our study shows that inhibition of ERK activation does not protect against TBHP‐induced mitochondrial dysfunction but promotes recovery of mitochondrial function by improving electron flow through the respiratory chain. Supported by NIH/NIDDK R01DK59558.