Over-expression of heme oxygenase-1 promotes oxidative mitochondrial damage in rat astroglia

✍ Scribed by Wei Song; Haixiang Su; Sisi Song; Hemant K. Paudel; Hyman M. Schipper

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 232 KB
• Volume: 206
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.20509

✦ Synopsis

Abstract

Glial heme oxygenase‐1 is over‐expressed in the CNS of subjects with Alzheimer disease (AD), Parkinson disease (PD) and multiple sclerosis (MS). Up‐regulation of HO‐1 in rat astroglia has been shown to facilitate iron sequestration by the mitochondrial compartment. To determine whether HO‐1 induction promotes mitochondrial oxidative stress, assays for 8‐__epi__PGF~2α~ (ELISA), protein carbonyls (ELISA) and 8‐OHdG (HPLC‐EC) were used to quantify oxidative damage to lipids, proteins, and nucleic acids, respectively, in mitochondrial fractions and whole‐cell compartments derived from cultured rat astroglia engineered to over‐express human (h) HO‐1 by transient transfection. Cell viability was assessed by trypan blue exclusion and the MTT assay, and cell proliferation was determined by [^3^H] thymidine incorporation and total cell counts. In rat astrocytes, hHO‐1 over‐expression (×3 days) resulted in significant oxidative damage to mitochondrial lipids, proteins, and nucleic acids, partial growth arrest, and increased cell death. These effects were attenuated by incubation with 1 µM tin mesoporphyrin, a competitive HO inhibitor, or the iron chelator, deferoxamine. Up‐regulation of HO‐1 engenders oxidative mitochondrial injury in cultured rat astroglia. Heme‐derived ferrous iron and carbon monoxide (CO) may mediate the oxidative modification of mitochondrial lipids, proteins and nucleic acids in these cells. Glial HO‐1 hyperactivity may contribute to cellular oxidative stress, pathological iron deposition, and bioenergetic failure characteristic of degenerating and inflamed neural tissues and may constitute a rational target for therapeutic intervention in these conditions. © 2005 Wiley‐Liss, Inc.