Abstract
Thiazolidinediones alter cell energy metabolism. They are used to treat or are being considered for the treatment of disorders that feature mitochondrial impairment. Their mitochondrial effects, however, have not been comprehensively studied under long-term exposure conditions. We used the human neuron-like NT2 cell line to directly assess the long-term effects of a thiazolidinedione drug, pioglitazone, on mitochondria. At micromolar concentrations, pioglitazone increased mitochondrial DNA (mtDNA) content, levels of mtDNA and nuclear-encoded electron transport chain subunit proteins, increased oxygen consumption, and elevated complex I and complex IV Vmax activities. Pioglitazone treatment was also associated with increased cytoplasmic but reduced mitochondrial peroxide levels. Our data suggest that pioglitazone induces mitochondrial biogenesis and show that pioglitazone reduces mitochondrial oxidative stress in a neuron-like cell line. For these reasons pioglitazone may prove useful in the treatment of mitochondriopathies.
Footnotes
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This research was funded by grants from Takeda Pharmaceuticals and the National Institute on Aging (AG022407).
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.106.033845.
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ABBREVIATIONS: PPARG, peroxisome proliferator activator receptor; PGC-1α, peroxisome proliferator-activated receptor (coactivator 1α); NRF-1, nuclear respiratory factor 1; ETC, electron transport chain; AD, Alzheimer's disease; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; PMSF, phenylmethylsulfonyl fluoride; HBSS, Hanks' buffered salt solution; mtDNA, mitochondrial DNA; NRF, normalized relative fluorescence; NT2, Ntera/D1; DTNB, 5,5′-dithio-bis (2-nitrobenzoic acid); DCF, 2′,7′-dichlorodihydrofluorescein diacetate; HRP, horseradish peroxidase; H2O2, hydrogen peroxide; GPx, glutathione peroxidase; DC, detergent compatible; DTT, dithiothreitol; TBS, Tris-buffered saline; PCR, polymerase chain reaction; ETC, electron transport chain.
- Received December 29, 2006.
- Accepted March 26, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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The Thiazolidinedione Pioglitazone Alters Mitochondrial Function in Human Neuron-Like Cells
