title: Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity: dual roles for ERK1/2.
abstract: The regulation of mitochondrial quality has emerged as a central issue in neurodegeneration, diabetes, and cancer. We utilized repeated low-dose applications of the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP(+)) over 2 weeks to study cellular responses to chronic mitochondrial stress. Chronic MPP(+) triggered depletion of functional mitochondria resulting in diminished capacities for aerobic respiration. Inhibiting autophagy/mitophagy only partially restored mitochondrial content. In contrast, inhibiting activation of extracellular signal-regulated protein kinases conferred complete cytoprotection with full restoration of mitochondrial functional and morphological parameters, enhancing spare respiratory capacity in MPP(+) co-treated cells above that of control cells. Reversal of mitochondrial injury occurred when U0126 was added 1 week after MPP(+), implicating enhanced repair mechanisms. Chronic MPP(+) caused a >90% decrease in complex I subunits, along with decreases in complex III and IV subunits. Decreases in respiratory complex subunits were reversed by co-treatment with U0126, ERK1/2 RNAi or transfection of dominant-negative MEK1, but only partially restored by degradation inhibitors. Chronic MPP(+) also suppressed the de novo synthesis of mitochondrial DNA-encoded proteins, accompanied by decreased expression of the mitochondrial transcription factor TFAM. U0126 completely reversed each of these deficits in mitochondrial translation and protein expression. These data indicate a key, limiting role for mitochondrial biogenesis in determining the outcome of injuries associated with elevated mitophagy.
authors.affiliation: Department of Pathology, Division of Neuropathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Zhu
authors.forename: A M
authors.initials: AM
authors.lastname: Gusdon
authors.forename: H
authors.initials: H
authors.lastname: Cimen
authors.forename: B
authors.initials: B
authors.lastname: Van Houten
authors.forename: E
authors.initials: E
authors.lastname: Koc
authors.forename: C T
authors.initials: CT
authors.lastname: Chu
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D001343:Autophagy; D045744:Cell Line, Tumor; D019069:Cell Respiration; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection
chemical_list: D024101:Mitochondrial Proteins; D048052:Mitogen-Activated Protein Kinase 3; D015655:1-Methyl-4-phenylpyridinium