title: Peroxisome proliferator activated receptor-γ agonists protect oligodendrocyte progenitors against tumor necrosis factor-alpha-induced damage: Effects on mitochondrial functions and differentiation.
abstract: The activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is known to exert anti-inflammatory and neuroprotective effects and PPAR-γ agonists are considered potential therapeutic agents in brain diseases including those affecting myelin. In demyelinating diseases such as multiple sclerosis (MS), inflammation is one of the causes of myelin and axonal damage. Oligodendrocyte (OL) differentiation is highly dependent on mitochondria, which are major targets of inflammatory insult. Here we show that PPAR-γ agonists protect OL progenitors against the maturational arrest induced by the inflammatory cytokine TNF-α by affecting mitochondrial functions. We demonstrate that the inhibition of OL differentiation by TNF-α is associated with i) increased mitochondrial superoxide production; ii) decreased mitochondrial membrane potential (mMP); and iii) decreased ADP-induced Ca(2+) oscillations, which we previously showed to be dependent on efficient mitochondria. The TNF-α effects were comparable to those of the mitochondrial toxin rotenone, further suggesting that TNF-α damage is mediated by mitochondrial function impairment. PPAR-γ agonists protected OL progenitors against the inhibitory activities of both TNF-α and rotenone on mMP, mitochondrial ROS production, Ca(2+) oscillations and OL differentiation. Finally, the PPAR-γ agonist pioglitazone increased the expression of PGC-1α (a mitochondrial biogenesis master regulator), UCP2 (a mitochondrial protein known to reduce ROS production), and cytochrome oxidase subunit COX1. These findings confirm the central role of mitochondria in OL differentiation and point to mitochondria as major targets of PPAR-γ agonist protection against TNF-α damage.
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Italy. Electronic address: chiara.denuccio@iss.it.
authors.forename: C
authors.initials: C
authors.lastname: De Nuccio
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bernardo
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Cruciani
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Italy.
authors.forename: R
authors.initials: R
authors.lastname: De Simone
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Visentin
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Minghetti
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007473:Ion Channels / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000494:pharmacology; D013234:Stem Cells; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000071246:Uncoupling Protein 2
chemical_list: D065168:Bradykinin Receptor Antagonists; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D047495:PPAR gamma; C120984:R 715; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D012402:Rotenone; D000255:Adenosine Triphosphate; D051545:Cyclooxygenase 1; C496513:Ptgs1 protein, rat; D001920:Bradykinin; D002118:Calcium; D000077205:Pioglitazone
keywords: Mitochondria; Multiple sclerosis; Oligodendrocytes; PGC-1α; PPAR-γ; TNF-α; UCP2