Abstract
Delayed neuronal cell death largely contributes to the progressive infarct development and associated functional impairments after cerebral ischemia or brain trauma. Previous studies exposed a key role for the interaction of the mitochondrial protein apoptosis-inducing factor (AIF) and cytosolic cyclophilin A (CypA) in pathways of programmed cell death in neurons in vitro and in vivo. These studies suggested that pro-apoptotic activities of AIF, such as its translocation to the nucleus and subsequent DNA degradation, depend on the physical interaction of AIF with CypA. Hence, this protein complex may represent a new pharmacological target for inhibiting the lethal action of AIF on the brain tissue. In this study, we show that the AIF amino-acid residues 370-394 mediate the protein complex formation of AIF with CypA. The synthetic AIF(370-394) peptide inhibited AIF/CypA complex formation in vitro by binding CypA with a K(D) of 12 μM. Further, the peptide exerted pronounced neuroprotective effects in a model of glutamate-induced oxidative stress in cultured HT-22 cells. In this model system of AIF-dependent cell death, the AIF(370-394) peptide preserved mitochondrial integrity, as detected by measurements of the mitochondrial membrane potential and quantification of mitochondrial fragmentation. Further, the AIF(370-394) peptide inhibited perinuclear accumulation of fragmented mitochondria, mitochondrial release of AIF to the nucleus and glutamate-induced cell death to a similar extent as CypA-siRNA. These data indicate that the targeting of the AIF-CypA axis is an effective strategy of neuroprotection.
Original language | English |
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Article number | e993 |
Number of pages | 12 |
Journal | Cell death & disease |
Volume | 5 |
DOIs | |
Publication status | Published - 2014 |
Externally published | Yes |
Keywords
- Amino Acid Motifs
- Apoptosis
- Apoptosis Inducing Factor
- Cyclophilin A
- Down-Regulation
- Humans
- Mitochondria
- Neurons
- Oxidative Stress
- Protein Binding
- NEURONAL CELL-DEATH
- OXYGEN-GLUCOSE DEPRIVATION
- FOCAL CEREBRAL-ISCHEMIA
- TRAUMATIC BRAIN-INJURY
- CYCLOPHILIN-A
- NUCLEAR TRANSLOCATION
- APOPTOSIS
- AIF
- MITOCHONDRIA
- NEUROPROTECTION