Abstract
Confocal microscopy images revealed that the tetratricopeptide repeat motif (TPR) domain immunophilin FKBP51 shows colocalization with the specific mitochondrial marker MitoTracker. Signal specificity was tested with different antibodies and by FKBP51 knockdown. This unexpected subcellular localization of FKBP51 was confirmed by colocalization studies with other mitochondrial proteins, biochemical fractionation, and electron microscopy imaging. Interestingly, FKBP51 forms complexes in mitochondria with the glucocorticoid receptor and the Hsp90/Hsp70-based chaperone heterocomplex. Although Hsp90 inhibitors favor FKBP51 translocation from mitochondria to the nucleus in a reversible manner, TPR domain-deficient mutants of FKBP51 are constitutively nuclear and fully excluded from mitochondria, suggesting that a functional TPR domain is required for its mitochondrial localization. FKBP51 overexpression protects cells against oxidative stress, whereas FKBP51 knockdown makes them more sensitive to injury. In summary, this is the first demonstration that FKBP51 is a major mitochondrial factor that undergoes nuclear-mitochondrial shuttling, an observation that may be related to antiapoptotic mechanisms triggered during the stress response.
Highlights
Trans-isomerase enzymatic activity in most of the members of the family and is the binding site of the drug
To determine whether FKBP51 is within mitochondria rather than associated with the outer membrane, purified mitochondria from 3T3-L1 fibroblasts were pretreated on ice for 10 min with 1% Triton X-100 followed by incubation with proteinase K
Western blots indicate that a substantial amount of mitochondrial FKBP51 is localized within the organelle of these cells (64.5 Ϯ 2.5%, a value normalized by cyclooxygenase IV (Cox-IV) signal, n ϭ 4)
Summary
Trans-isomerase enzymatic activity in most of the members of the family and is the binding site of the drug. FKBP51 Localizes in Mitochondria in Several Cell Types— Fig. 1A shows confocal microscopy images of FKBP51 in 3T3-L1 fibroblasts suggesting the mitochondrial localization of this immunophilin.
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