Premium
ERK2 translocates to mitochondria during neurodegeneration and is associated with mitochondrial autophagy.
Author(s) -
Dagda Ruben Karim,
Zhu Jianhui,
Kulich Scott M.,
Chu Charleen T.
Publication year - 2007
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.21.5.a23-d
Subject(s) - microbiology and biotechnology , neurodegeneration , mitochondrion , autophagy , mitophagy , colocalization , biology , transfection , green fluorescent protein , cytoplasm , programmed cell death , apoptosis , cell culture , biochemistry , pathology , medicine , genetics , disease , gene
We have previously shown that neurons of post‐mortem brain tissue from Parkinson's Disease (PD) patients contain cytoplasmic granules of phosphorylated extracellular signal regulated kinase (ERK) that partially localize to mitochondria in autophagosomes (Zhu et al, 2003). We utilized biochemical and imaging approaches to determine whether ERK activation is associated with mitochondrial localization in experimental models of PD. Subcellular fractionation of B65 cells treated with 6‐hydroxydopamine revealed a pool of phosphorylated ERK2 contained in mitochondria‐enriched fractions. SH‐SY5Y cells expressing different GFP fusion proteins of ERK2, or GFP alone, were also analyzed for colocalization with mitochondria. Under basal conditions, confocal microscopy revealed that cells transfected with constitutively active ERK2‐GFP, but not wild‐type‐ERK2‐GFP, showed increased cell death and displayed discrete cytoplasmic ERK2 granules of which a small fraction colocalized with mitochondrial or lysosomal markers. However, treatment with neurotoxins, or with bafilomycin, an inhibitor of autophagosome fusion with lysosomes, robustly increased the number and size of granules in wild‐type‐ERK2‐GFP. Our studies support the hypothesis that mitochondrial ERK2 may promote mitophagy, with dysregulation of this process contributing to neurodegeneration in PD.