DOI 10.1515/hsz-2013-0152      Biol. Chem. 2013; 394(12): 1607–1614

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Antonietta Bernardo, Roberta De Simone, Chiara De Nuccio, Sergio Visentin and Luisa Minghetti*

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

Abstract: Peroxisome proliferator-activated receptor-γ (PPAR-γ) is one of the most studied nuclear receptor since its identification as a target to treat metabolic and neuro-logical diseases. In addition to exerting anti-inflammatory and neuroprotective effects, PPAR-γ agonists, such as the insulin-sensitizing drug pioglitazone, promote the differ-entiation of oligodendrocytes (OLs), the myelin-forming cells of the central nervous system (CNS). In addition, PPAR-γ agonists increase OL mitochondrial respiratory chain activity and OL’s ability to respond to environmen-tal signals with oscillatory Ca2+ waves. Both OL maturation and oscillatory Ca2+ waves are prevented by the mitochon-drial inhibitor rotenone and restored by PPAR-γ agonists, suggesting that PPAR-γ promotes myelination through mechanisms involving mitochondria.

Keywords: Ca2+ waves; mitochondria; myelin; oligodendro-cytes; pioglitazone; rotenone.

*Corresponding author: Luisa Minghetti, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy, e-mail: luisa.minghetti@iss.itAntonietta Bernardo, Roberta De Simone, Chiara De Nuccio and Sergio Visentin: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy

Introduction: structure, functions and distribution of PPARsThe PPARs belong to the superfamily of the nuclear receptors (NRs), a heterogeneous class of transcription factors that regulate gene expression in response to a broad array of physiological stimuli. The three members

of the PPAR family (PPAR-α, PPAR-β/δ and PPAR-γ) share a high homology and a similar organization in five dif-ferent functional domains, two of which – the DNA-bind-ing domain and the ligand-binding domain (Figure  1A and B) – are highly conserved among species (Willson et al., 2000). The DNA-binding domain contains the two zinc finger-like motifs that recognize the DNA target and that can be considered the hallmark of the NR super-family. The ligand-binding domain is characterized by a three-dimensional structure, which defines a particu-larly large ligand-binding cavity, conserved among the three members. This domain serves several important functions as it not only binds the ligand but also medi-ates interactions with co-activators and co-repressors in highly specific ways. Furthermore, the binding of the ligand triggers conformational changes at the binding domain that allows the formation of heterodimers with the retinoid X receptor (RXR). The PPAR-RXR heterodi-mers, through the zinc finger-like motifs, interact with specific PPAR response elements (PPREs) in the promoter region of PPAR-target genes, leading to either activation or repression of their expression (Figure 1A). PPARs may also control gene expression independently of PPRE binding, through a mechanism termed transrepression, not yet fully elucidated, that involves the stabilization of complexes between specific transcription factors, e.g., NF-κB, and their co-repressors (Glass and Saijo, 2010). Alternatively, transrepression could be achieved by post-translational modifications of PPARs – in particular of PPAR-γ – by SUMOylation, a process by which the small ubiquitin-like modifier SUMO is covalently conjugated to lysine residues of target proteins (Ghisletti et al., 2007).

The PPARs are ubiquitously expressed although they show specific pattern distribution. PPAR-α is expressed mainly in tissues with high catabolic rates of fatty acids, such as liver, muscle and heart. PPAR-β/δ is present in a

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1608      A. Bernardo et al.: PPAR-γ, mitochondria and oligodendrocytes

wide range of tissues (heart, adipose tissue, brain, intes-tine, muscle, spleen, lung and adrenal glands). Finally, PPAR-γ is highly expressed in adipose tissue, in immune system cells (lymphocytes and macrophages), and in the brain, where it is found in microglia, astrocytes, oligo-dendrocytes, and neurons (Bernardo and Minghetti, 2008 and references therein). All three PPARs are involved in the control of metabolism homeostasis but they also are

implicated in development, reproduction, inflammation, immunity and cell differentiation.

PPAR-γ and its agonistsPPAR-γ has been one of the most studied NRs since its identification as a drugable target to treat metabolic

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Figure 1 PPAR-γ agonist promotes oligodendrocyte differentiation. A, Ligand-dependent activation, dimerization and nuclear translocation of PPAR-γ. B Schematic representation of the five structural domains composing PPAR-γ: A/B, including a ligand-independent activation function 1(AF-1); C, corresponding to the DNA-binding domain (DBD); E, comprising the ligand-binding domain (LBD). The domains C and D are separated by a hinge or D region, which is the target of post-translational modifications such as phosphorylation and sumoylation. C, OL maturation stages as defined by morphology and expression of specific markers: A2B5, identifying glial progenitors; PDGF-Rα, platelet-derived growth factor-receptor; O4, membrane ganglioside; CNP, 2′,3′-cyclic nucleotide 3′-phosphodiesterase; GalC (O1), galactocerebro-side;. MBP, myelin basic protein; MAG, microtubule-associated protein. D, OL progenitors (OPs), purified from neonatal rat brain mixed glial cultures, express PPAR-γ. PPAR-γ agonists (1 μm for 24 h) induced nuclear localization of the receptor (inset, left panel), and increased its expression (densitometric analysis of Western blots, right panel). E, OPs treated with 15d-PGJ2 (1 μm for 24 h), show higher percentage of O1+ cells (mature OL). The effect was reverted by the PPAR-γ antagonist GW9662. F, The PPAR-γ agonist 15d-PGJ2 (1 μm for 24 h or 72 h) increases the levels of transcripts encoding for the 18.5 and 21.5 kDa MBP isoforms (RNA protection assay).

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A. Bernardo et al.: PPAR-γ, mitochondria and oligodendrocytes      1609

diseases such as type II diabetes. Furthermore, in the last decade, there has been an increasing interest for PPAR-γ because of the accumulating evidence to support a therapeutic potential of PPAR-γ agonists in a variety of brain disorders, including neurodegenerative diseases, traumatic injuries, stroke, and demyelinating diseases ( Bernardo and Minghetti, 2006; Heneka et al., 2007).

PPAR-γ is activated by both naturally occurring com-pounds, such as long-chain fatty acids and the 15-deoxy 12,14 prostaglandin J2 (15d-PGJ2), and by synthetic ago-nists, among which are some non-steroidal anti-inflamma-tory drugs and the anti-diabetic drugs thiazolidinediones (TZDs). The broad range of structurally different mole-cules with PPAR-γ agonistic activity can be explained by the large ligand-binding cavity of PPAR-γ, which allows a relatively free non-specific interaction with the ligand.

Thiazolidinediones are among the most potent and selective PPAR-γ full agonists. They were originally iden-tified as insulin-sensitizing agents in diabetic animals and came to market in the 1990s. Among the approved TZDs are pioglitazone (Actos) and rosiglitazone (Avandia), currently in use for the treatment of type-2 diabetes, and troglitazone (Rezulin), which was subse-quently withdrawn for safety concerns. In 2007, the FDA issued a report describing the potential risk of ischemic cardiovascular events for rosiglitazone and later, in 2010, its use was recommended only for patients who cannot control diabetes with other medications. Although these concerns were not extended to pioglitazone, a recent study identified an increased risk of bladder cancer asso-ciated with long term pioglitazone exposure in a French cohort of diabetic patients (Neumann et  al., 2012). The study led the French medicines agency to suspend the use of medications containing pioglitazone in June 2011. Because of the adverse effects and serious concerns, several recently developed PPAR-γ agonists have failed to progress to drug agency approval (Cariou et al., 2012). The need of clinically safe PPAR-γ agonists has fostered the search for alternative strategies for targeting PPAR-γ. Recently, a new class of agonists, named ‘selective mod-ulators of PPAR-γ activity’ (SPPARγMs), has attracted great interest. SPPARγMs retain the biological activities of classical ligands while reducing unwanted effects by virtue of their ability to induce alternative PPAR-γ con-formational changes, which result in distinct recruit-ment/displacement of co-factors and in differential gene expression. Among SPPARγMs is the marketed angio-tensin receptor antagonist telmisartan, which acts as partial PPAR-γ agonist with selective cofactor binding and a differential gene expression profile as compared to rosiglitazone. As a result, in animal models, telmisartan

improves the insulin sensitivity without causing weight gain (Zhang et al., 2007).

PPAR-γ, oligodendrocyte matura-tion and myelin formationOligodendrocytes (OLs) are the myelin-forming cells of the CNS. Their differentiation from precursor to mature cells occurs through a series of stages that can be defined by morphological and antigenic changes occurring in vivo as well as in culture systems (Levi et al., 1987). As schemati-cally summarized in Figure 1C, precursor and progenitor cells are small cells with few processes. Oligodendrocyte progenitors (OP), express surface gangliosides recognized by the monoclonal antibodies A2B5 and LB1. As differen-tiation proceeds, cells acquire a number of processes that become highly branched in mature OLs and begin to express myelin proteins, among which the myelin basic protein (MBP) is one of the most abundant. During deve-lopment and repair, OL processes extend and form multi-lamellar sheaths around neuronal axons.

The formation, growth, and maintenance of the myelin sheath are prominent parts of neural development and nervous system function. Damage to OLs as a result of oxidative stress is considered a key pathogenetic pathway in several adult and infant human diseases. A substan-tial number of in vitro and in vivo studies have shown a maturation-dependent vulnerability to oxidative stress of the OL lineage (Back et al., 2002; Bernardo et al., 2003), suggesting that OL progenitor is a key target for limit-ing white matter damage and promoting myelin repair (Zawadzka and Franklin, 2007).

Oligodendrocytes are major lipid-producing cells, as required for myelin formation and maintenance. Given the role of PPARs in lipid metabolism it is conceivable that this group of NRs plays a role in OL differentiation and function. Although PPAR-β/δ is considered the PPAR type mainly expressed in OLs and involved in myelina-tion (Granneman et al., 1998; Saluja et al., 2001), recent findings support the involvement of PPAR-γ activators in OL protection and differentiation. The first evidence was reported by Roth et al. (2003), using the B12 oligodendro-cyte-like cell line and primary cultures of spinal cord OL precursors as experimental models. Although all three PPAR isoforms were found expressed in these cells, only PPAR-γ agonists enhanced process extension and cell mat-uration. The effects were blocked by the PPAR-γ antagonist GW9662 supporting the specific involvement of PPAR-γ. The maturation of pre-OLs was accompanied by enhanced

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1610      A. Bernardo et al.: PPAR-γ, mitochondria and oligodendrocytes

expression of alkyl-dihydroxyacetone phosphate synthase (ADAPS), a peroxisomal enzyme required for the synthe-sis of plasmalogen, an etherphospholipid essential for myelin formation, suggesting that PPAR-γ mediated mech-anisms may be important for OL differentiation and per-oxisome functions. In line with these results, we reported the expression of PPAR-γ in highly purified cultures of OPs from rat cortex (Bernardo et al., 2009). Using this experi-mental model (recapitulating OL maturation from OP to mature OL though 1–7 days in vitro; see box in Figure 1C), we have shown that PPAR-γ is expressed by cells of the OL lineage from the early stages of development (O4 negative OP) and its expression levels are increased by the specific agonists pioglitazone and 15d-PGJ2. The two agonists also inhibit OP proliferation and promote their differentiation towards OLs, through PPAR-γ dependent mechanisms as indicated by the increased fraction of O1-positive cells after 24 h of agonist treatment. The positive effect on OL maturation was more evident after repeated administra-tions of PPAR-γ agonists to OP cultures. When compared to cultures of the same age (4 DIV), PPAR-γ treated cul-tures exhibit an increased number of O4, O1 and MBP-positive cells. In parallel with the increased number of MBP+ cells, the levels of transcripts encoding for the 18.5 and 21.5 MBP isoforms are also enhanced. In particular, the 21.5 kDa isoform, which appears earlier during deve-lopment 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).

PPAR-γ agonist-induced oligodendro cyte differentiation: involvement of Ca2+ waves and mitochondrial functionsReceptor mediated reactions affecting Ca2+ homeostasis contribute to regulating the differentiation of cells belong-ing to the OL lineage, and in such a way they concur to white matter development and re-myelination. The co-localization of endoplasmic reticulum (ER) and mitochon-dria and site-specific interactions between their opposite membranes have great impact on the physiology of both compartments as well as on Ca2+ signalling. Mitochondria play a significant role in Ca2+ signalling by virtue of their capability to uptake and release Ca2+, and to produce a

number of factors (e.g., ATP and reactive oxygen species, ROS), which may contribute to Ca2+ signalling regula-tion (see Figure 2A; Brookes et al., 2004, and references therein).

The mitochondrial regulation of Ca2+ raise and Ca2+ wave propagation is not univocal, as mitochondria can either inhibit or amplify Ca2+ onset and wave propagation (Walsh et al., 2009, and reference therein). In developing OLs, mitochondria act as amplifiers of Ca2+ movements (Haak et al., 2000) and control the Ca2+ oscillatory events, as supported by the significant correlation between ADP-induced Ca2+ oscillations and the presence of mitochon-dria (Figure 2B and C; De Nuccio et al., 2011). In PPAR-γ agonist-treated OLs, both the amplitude of cytoplasmic Ca2+ signals and probability of occurrence of the oscilla-tory events are increased (Figure 2D). Again, the spatial correlation between sites of Ca2+ oscillation with higher frequency and the presence of mitochondria along OL pro-cesses strongly suggests that mitochondria are involved in the effects induced by PPAR-γ agonists, although the con-tribution of other mechanisms cannot be ruled out (De Nuccio et al., 2011).

As mentioned above, among the mitochondrial events that can potentially influence cytoplasmic Ca2+ transients and that could be affected by PPAR-γ agonists, are Ca2+ uptake/release and the production of molecules such as ATP and ROS. In addition, PPAR-γ agonists could influence the inner mitochondrial membrane potential (mMP), by which ATP synthesis, ROS production and Ca2+ uptake are tightly controlled. In our experimental condi-tions, PPAR-γ agonist treatment did not affect mitochon-drial membrane potential but it increased the activity of the respiratory chain complex IV (cytochrome oxidase), which is responsible for the final steps of the electron flux through the respiratory chain and the reduction of O2 to H2O (Figure 3). Figure 3A and B show a schematic repre-sentation of the organization of the component of the res-piratory chain and an example of the increased complex IV activity, respectively.

Mild inhibition of mitochondrial respiratory chain complex I and complex IV by rotenone or sodium azide, respectively, has been reported to impair OL matura-tion (Schoenfeld et  al., 2010; Ziabreva et  al., 2010). In addition, we have found that rotenone, besides slowing down OL differentiation, decreases Ca2+ oscillations and that PPAR-γ agonists are capable of counteracting the rotenone-dependent impairment of both differentiation and Ca2+ oscillatory activity (Figure 3C), further support-ing the need of functional mitochondria for the Ca2+ oscil-latory behaviour and the proper accomplishment of OL maturation (De Nuccio et al., 2011). Taken together, these

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A. Bernardo et al.: PPAR-γ, mitochondria and oligodendrocytes      1611

observations suggest that the increased activity of respira-tory chain promoted by PPAR-γ agonists could result in an augmented ATP production and availability for ATP-dependent events ultimately linked to Ca2+ oscillations. Two ATP-dependent events affecting Ca2+ signalling are Ca2+ uptake by the sarcoplasmic endoplasmic reticulum Ca2+ ATPase (SERCA), and activation of ER Ca2+ permeable IP3 receptors (Figure 2A). Inhibition of SERCA was shown to convert oscillatory Ca2+ signals in a sustained Ca2+ raise (Wood et al., 1993); while IP3 receptor type 1, which is the most sensitive to ATP and is capable of mediating Ca2+ oscillations (Miyakawa et  al., 1999), is transiently expressed in developing fiber tracts, probably by OLs at the onset of myelination (Dent et al., 1996).

Features of Ca2+ signalling, such as concentration of the ion, timing, compartmentalization and frequency of oscillations, compose a signalling code that allows a

sophisticated and specific control of a multitude of cellu-lar events (Berridge et al., 2003, and references therein). Transient rises of Ca2+ concentration, organized as oscilla-tory events and used as a frequency code, are more suita-ble for signalling than sustained Ca2+ transients, given the deleterious effects of a prolonged Ca2+ raise. In this light, PPAR-γ agonist-dependent enhancement of Ca2+ oscilla-tions may play specific roles in the ensemble of events supporting OL differentiation.

Among the possible mechanisms, Ca2+ oscillations could adapt the mitochondrial activity to the required energetic needs of OL differentiation by enhancing the availability of reduced equivalents (i.e., NADH, FADH2) as a number of mitochondrial dehydrogenases are Ca2+ dependent and in particular, as in the case of pyruvate dehydrogenase, they are especially dependent on Ca2+ oscillations (Robb-Gaspers et al., 1998).

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Figure 2 Effect of PPAR-γ agonists on Ca2+ movements in oligodendrocytes and the role of mitochondria. A, Schematic representation of the role played by mitochondria in the control of calcium homeostasis upon activation of a G protein-coupled receptor, as P2Y1 recep-tor by the specific agonist (ADP). Mitochondria, acting as calcium store, uptake the Ca2+ released from the ER, Ca2+ uptake affects several mitochondrial functions such as the synthesis of ATP, in turn influencing the activity of SERCA pump and IP3R. B, Monophasic and oscillatory Ca2+ transients induced by ADP, P2Y1 agonist, in OLs (video imaging experiments with the Ca2+ probe Fluo3). C, Recording of oscillatory Ca2+ transients and position of mitochondria along OL processes, by means of the dyes Fluo3 and TMRE, respectively revealed higher frequency of oscillations in regions containing mitochondria. D, PPAR-γ agonist 15d-PGJ2 (1 μm for 24 h) increased both the amplitude and fraction of oscillating processes compared to control conditions (*p < 0.05).

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1612      A. Bernardo et al.: PPAR-γ, mitochondria and oligodendrocytes

Ca2+ oscillations could also facilitate OL differentia-tion by inducing mitochondrial gene transcription and biogenesis. For example, the differentiation of slow-twitch myofibers requires a particular time-course of Ca2+ changes to activate Ca2+-calmodulin-dependent kinases CaMKII and CaMKIV, which lead to mitochondrial biogen-esis and induction of oxidative enzymes. These effects are mediated by mechanisms involving the CREB-mediated expression of PGC-1α, one of the most important co-activators of PPAR-γ and inducers of mitochondrial bio-genesis (Chin, 2004). Preliminary observations indicate that 24 h treatment of OPs with the PPAR-γ agonists 15d-PGJ2 or pioglitazone increases the expression of PGC-1α

(Bernardo et al., unpublished observation), which could ultimately lead to the biogenesis of mitochondria, and in turn, to the observed increase of complex IV activity and recovery from rotenone effects (Figure 3).

ConclusionsIn the last decade, PPAR-γ agonists have been increasingly considered for their therapeutic potential in a wide range of neurological diseases, including demyelinating dis-eases. Although the beneficial effects of PPAR-γ agonists

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Figure 3 PPAR-γ agonists promote the activity of the mitochondrial Complex IV and prevent rotenone effects. A, Schematic representation of the mitochondrial respiratory chain. Electrons flow from NADH and FADH2 along the respiratory chain to complex (Cx) IV where oxygen is reduced to H2O. The resulting energy is used to pump protons from the matrix to the intermembrane space (IMS), generating the proton gra-dient required for ATP synthesis. Electrons flowing along the chain may also reduce oxygen to superoxide ion -

2(O ) at Cx I and III. Adenine nucleotide translocase (ANT) and voltage-dependent anion channels (VDAC) allow the translocation of ATP and ADP across mitochondrial membranes. B, Complex IV histochemistry in OL cultures, after 72 h in the absence (ctr) or in the presence of 15d-PGJ2 or pioglitazone. Brown staining indicating Cx IV activity was completely abrogated when cells were exposed to sodium azide (NaN3), 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. C, Cells were maintained for 72 h in the presence of rotenone (10 nm), a Cx I inhibitor, with or without pioglitazone. Cell viability (by MTT assay), Ca2+ transients and OL differentiation (O4

+ cells) were then assessed. *p < 0.05 vs. control; **p < 0.05 vs. rotenone. ANT, adenine nucleotide translocase; CL, cardiolipin; CytC, cytochrome C; CoQ, coenzyme Q; IM, inner membrane; IMS, inter-membrane space; OM outer membrane; VDAC, voltage-dependent anion channel.

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A. Bernardo et al.: PPAR-γ, mitochondria and oligodendrocytes      1613

have been largely attributed to their ability to reduce inflammation and glial activation, we have provided evi-dence that they may directly affect OPs and support their differentiation to mature OLs. Our observations suggest that PPAR-γ agonists promote myelination through mech-anisms that enhance mitochondrial functions such as the respiratory chain activity and their ability to sustain oscil-latory Ca2+ waves. A better understanding of the role of PPAR-γ and its agonists in OL biology is important to fully

exploit the therapeutic potential of PPAR-γ agonist for the treatment of diseases in which mitochondrial alterations and demyelination take place.

Acknowledgments: This study was supported by FISM – Fondazione Italiana Sclerosi Multipla, Grant 2011/R/15.

Received March 22, 2013; accepted June 13, 2013; previously published online June 14, 2013

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