Peroxisome Proliferator-Activated Receptor γ Agonists Accelerate Oligodendrocyte Maturation and Influence Mitochondrial Functions and Oscillatory Ca²⁺Waves

Abstract

We have previously shown that natural (15-deoxy-Δ-prostaglandin J2) and synthetic (pioglitazone) agonists of peroxisome proliferator-activated receptor γ (PPAR-γ) strengthen the intrinsic cellular mechanisms protecting oligodendrocyte (OL) progenitors (OPs) from oxidative insults and promote their differentiation. Here, we demonstrate that repeated administrations of PPAR-γ agonists to OP cultures accelerate their differentiation to OLs, as indicated by increased numbers of O4- and O1-positive cells that show increased myelin basic protein expression, elaborated cholesterol-enrichedmembranes and have increased peroxisomes. Moreover, PPAR-γ agonist-treated OLs show increased activity of the mitochondrial respiratory chain Complex IV and an increased ability to respond to environmental signals, such as adenosine diphosphate (ADP), with oscillatory Ca waves; the latter closely correlated with the presence of mitochondria and were inhibited by the mitochondrial respiratory chain Complex I inhibitor rotenone. Because Ca oscillations and mitochondrial respiratory chain activity play crucial roles in OL differentiation, these findings suggest that PPAR-γ agonists could protect OLs and promote myelination through several mechanisms, including those involving mitochondrial functions. Our studies support the therapeutic potential of PPAR-γ agonists in brain diseases in which mitochondrial alteration, oxidative stress, and demyelination occur and point to the need for a better understanding of the role of PPAR-γ and its agonists in OL biology.

The nuclear receptor peroxisome proliferator-activated receptor-γ promotes oligodendrocyte differentiation through mechanisms involving mitochondria and oscillatory Ca2+ waves

“…In developing OLs, mitochondria act as amplifiers of Ca 2+ movements (Haak et al, 2000) and control the Ca 2+ oscillatory events, as supported by the significant correlation between ADPinduced Ca 2+ oscillations and the presence of mitochondria (Figure 2B and C;De Nuccio et al, 2011). In PPAR-γ agonist-treated OLs, both the amplitude of cytoplasmic Ca 2+ signals and probability of occurrence of the oscillatory events are increased ( Figure 2D).…”

“…In addition, we have found that rotenone, besides slowing down OL differentiation, decreases Ca 2+ oscillations and that PPAR-γ agonists are capable of counteracting the rotenone-dependent impairment of both differentiation and Ca 2+ oscillatory activity ( Figure 3C), further supporting the need of functional mitochondria for the Ca 2+ oscillatory behaviour and the proper accomplishment of OL maturation (De Nuccio et al, 2011). Taken together, these observations suggest that the increased activity of respiratory chain promoted by PPAR-γ agonists could result in an augmented ATP production and availability for ATPdependent events ultimately linked to Ca 2+ oscillations.…”

“…Brown staining indicating Cx IV activity was completely abrogated when cells were exposed to sodium azide (NaN 3 ), before performing the staining (not shown), indicating the specific respiratory chain activity. For further details see De Nuccio et al (2011). Scale bar = 25 μm.…”

“…In PPAR-γ agonist-treated OLs, both the amplitude of cytoplasmic Ca 2+ signals and probability of occurrence of the oscillatory events are increased ( Figure 2D). Again, the spatial correlation between sites of Ca 2+ oscillation with higher frequency and the presence of mitochondria along OL processes strongly suggests that mitochondria are involved in the effects induced by PPAR-γ agonists, although the contribution of other mechanisms cannot be ruled out (De Nuccio et al, 2011).…”

“…In particular, the 21.5 kDa isoform, which appears earlier during development and is expressed mainly during myelinogenesis (Baumann and Pham-Dinh, 2001), was the most affected by the agonists (Figure 1D-F). The accelerated maturation is further indicated by the characteristic morphology with elaborated membrane extensions of mature OLs, typically found in older cultures (De Nuccio et al, 2011).…”