Mitochondrial Dynamics-related Proteins Research Articles

DAP3 Is Involved in Modulation of Cellular Radiation Response by RIG-I-Like Receptor Agonist in Human Lung Adenocarcinoma Cells.

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) mediate anti-viral response through mitochondria. In addition, RLR activation induces anti-tumor effects on various cancers. We previously reported that the RLR agonist Poly(I:C)-HMW/LyoVec™ (Poly(I:C)) enhanced radiosensitivity and that cotreatment with Poly(I:C) and ionizing radiation (IR) more than additively increased cell death in lung adenocarcinoma cells, indicating that Poly(I:C) modulates the cellular radiation response. However, it remains unclear how mitochondria are involved in the modulation of this response. Here, we investigated the involvement of mitochondrial dynamics and mitochondrial ribosome protein death-associated protein 3 (DAP3) in the modulation of cellular radiation response by Poly(I:C) in A549 and H1299 human lung adenocarcinoma cell lines. Western blotting revealed that Poly(I:C) decreased the expression of mitochondrial dynamics-related proteins and DAP3. In addition, siRNA experiments showed that DAP3, and not mitochondrial dynamics, is involved in the resistance of lung adenocarcinoma cells to IR-induced cell death. Finally, we revealed that a more-than-additive effect of cotreatment with Poly(I:C) and IR on increasing cell death was diluted by DAP3-knockdown because of an increase in cell death induced by IR alone. Together, our findings suggest that RLR agonist Poly(I:C) modulates the cellular radiation response of lung adenocarcinoma cells by downregulating DAP3 expression.

Effects of Recombinant Human Erythropoietin on Inflammatory Factors in Rats with Traumatic Brain Injury

To study the effects of recombinant human erythropoietin on inflammatory factors in rats with traumatic brain injury is the main objective. A total of 45 specific-pathogen-free grade male Sprague-Dawley rats were randomly assigned into sham operation group (sham group), model group and recombinant human erythropoietin intervention group (treatment group) (n=15). Model and treatment groups were prepared into traumatic brain injury model by hitting the head through the modified Feeney’s free-fall impact method, while the head of sham group was not hit. After modeling, treatment group was intraperitoneally injected with recombinant human erythropoietin at 5000 IU/kg daily and sham and model groups were intraperitoneally injected with the same dose of normal saline. The rats were killed after 7 d of continuous administration. The changes of brain mitochondrial membrane potential were detected through rhodamine 123 staining and immunocytochemistry and Western blotting were separately employed to measure the expressions of interleukin-1β, interleukin-6 and tumor necrosis factor-α in brain tissues and the expression levels of dynamin-related protein 1, fission 1, mitofusin 2 and optic atrophy 1, mitochondrial dynamics related proteins in brain tissues. Compared with sham group, model group exhibited significantly weakened rhodamine 123 fluorescence intensity, increased expressions of interleukin-1β, interleukin-6 and tumor necrosis factor-α, dynamin-related protein 1 and fission 1 and reduced expressions of mitofusin 2 and optic atrophy 1 in brain tissues (p<0.05). In comparison with model group, treatment group had significantly enhanced rhodamine 123 fluorescence intensity, reduced expressions of interleukin-1β, interleukin-6 and tumor necrosis factor-α, dynamin-related protein 1 and fission 1 and elevated expressions of mitofusin 2 and optic atrophy 1 in brain tissues (p<0.05). Recombinant human erythropoietin can protect the brain after traumatic brain injury by relieving the inflammatory response and mitochondrial injury after traumatic brain injury.

Research progress on potential targets-mitochondrial dynamics-related proteins in treatment of myocardial ischemia-reperfusion injury

Acute myocardial infarction(AMI) is still the leading cause of death worldwide. At present, the treatment of AMI is mainly to restore the cardiac blood supply through myocardial reperfusion. With the widespread use of coronary artery bypass grafting and percutaneous coronary intervention(PCI), myocardial reperfusion injury is a major clinical problem. Mitochondrial dysfunction is an important pathological basis for myocardial ischemic injury. Therefore, mitochondria can be used as an important target against myocardial damage. In this article, we would briefly review the physiological functions of mitochondrial dynamics-related proteins as well as their pathological mechanisms and pharmacological interventions in treatment of myocardial ischemia-reperfusion injury.

High-Intensity Interval Training Restores Glycolipid Metabolism and Mitochondrial Function in Skeletal Muscle of Mice With Type 2 Diabetes

High-intensity interval training has been reported to lower fasting blood glucose and improve insulin resistance of type 2 diabetes without clear underlying mechanisms. The purpose of this study was to investigate the effect of high-intensity interval training on the glycolipid metabolism and mitochondrial dynamics in skeletal muscle of high-fat diet (HFD) and one-time 100 mg/kg streptozocin intraperitoneal injection-induced type 2 diabetes mellitus (T2DM) mice. Our results confirmed that high-intensity interval training reduced the body weight, fat mass, fasting blood glucose, and serum insulin of the T2DM mice. High-intensity interval training also improved glucose tolerance and insulin tolerance of the T2DM mice. Moreover, we found that high-intensity interval training also decreased lipid accumulation and increased glycogen synthesis in skeletal muscle of the T2DM mice. Ultrastructural analysis of the mitochondria showed that mitochondrial morphology and quantity were improved after 8 weeks of high-intensity interval training. Western blot analysis showed that the expression of mitochondrial biosynthesis related proteins and mitochondrial dynamics related proteins in high-intensity interval trained mice in skeletal muscle were enhanced. Taken together, these data suggest high-intensity interval training improved fasting blood glucose and glucose homeostasis possibly by ameliorating glycolipid metabolism and mitochondrial dynamics in skeletal muscle of the T2DM mice.

Suppression of osteogenic differentiation and mitochondrial function change in human periodontal ligament stem cells by melatonin at physiological levels.

N-Acetyl-5-methoxytryptamine (melatonin, MT) at pharmacological concentrations promotes the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells; however, its role at physiological concentrations (1 pM–10 nM) remains unclear. We explored the effects of 1 pM–1 µM MT on the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and its underlying mitochondrial dynamics-mediated mechanisms. T he PDLSC phenotype was detected by flow cytometry and evaluated for three-line differentiation. Alkaline phosphatase activity assay and Alizarin red staining were used to evaluate osteogenic differentiation. Osteogenesis-related gene and protein expression levels were measured by quantitative reverse transcription -polymerase chain reaction and western blotting. Mitochondrial function assays were performed using reactive oxygen species, ATP and NAD+/NADH kits and molecular mechanisms of mitochondrial dynamics-related proteins were assessed by western blotting. Our results have shown that physiological MT concentrations induced differentiation of hPDLSCs and down-regulated osteopontin (OPN) and osteocalcin (OCN) expression levels, which were restored or even up-regulated by 1 µM MT (lowest pharmacological concentration). Compared to the osteogenic induction alone, this treatment decreased the intracellular ATP content, whereas the intracellular reactive oxygen species level and NAD+/NADH ratio were increased. Mitochondrial function- and dynamics-related protein expression levels were consistent with those of osteogenic genes following osteogenic induction and MT treatment of hPDLSCs at various physiological concentrations. Physiological MT concentrations inhibited the osteogenic differentiation of hPDLSCs and simultaneously altered mitochondrial function. These findings provide insights into the stem cell tissue engineering and functions of MT.

FGF21 Mediates Mesenchymal Stem Cell Senescence via Regulation of Mitochondrial Dynamics

Mesenchymal stem cell- (MSC-) based therapy is a novel strategy in regenerative medicine. The functional and regenerative capacities of MSCs decline with senescence. Nonetheless, the potential mechanisms that underlie their senescence are not fully understood. This study was aimed at exploring the potential mechanisms of fibroblast growth factor 21 (FGF21) in the regulation of MSC senescence. The senescence of MSCs was determined by senescence-associated β-galactosidase (SA-β-gal) staining. The morphology and the level of mitochondrial reactive oxygen species (ROS) of MSCs were assessed by MitoTracker and Mito-Sox staining, respectively. The expression of FGF21 and mitochondrial dynamics-related proteins was detected by Western blotting. As MSCs were expanded in vitro, the expression of FGF21 decreased. Depletion of FGF21 enhanced production of mitochondrial reactive oxidative species (ROS) and increased the senescence of early-passage MSCs whereas inhibition of ROS abolished these effects. The senescent MSCs exhibited increased mitochondrial fusion and decreased mitochondrial fission. Treatment of early-passage MSCs with FGF21 siRNA enhanced mitochondrial fusion and reduced mitochondrial fission. Moreover, treatment of mitofusin2- (Mfn2-) siRNA inhibited depletion of FGF21-induced MSC senescence. Furthermore, we demonstrated that depletion of FGF21-induced mitochondrial fusion was regulated by the AMPK signaling pathway. Treatment with an AMPK activator, AICAR, abrogated the depletion of FGF21-induced senescence of MSCs by inhibiting mitochondrial fusion. Compared with MSCs isolated from young donors, those derived from aged donors showed a lower level of FGF21 and a higher level of senescent activity. Furthermore, overexpression of FGF21 in aged MSCs inhibited senescence. Our study shows that FGF21, via the AMPK signaling pathway, regulates the senescence of MSCs by mediating mitochondrial dynamics. Targeting FGF21 might represent a novel strategy to improve the quality and quantity of MSCs.

Altered mitochondrial dynamics induced endothelial cell dysfunction and increased atherosclerosis in the mouse

Mitochondria are dynamic organelles altering their inner and outer membranes through fission and fusion mechanisms. In a response to shear stress, the mitochondria in endothelial cells (ECs) continuously undergo fusion and fission mechanisms. We hypothesized that alteration in mitochondria dynamic could alter EC functions leading to vascular damage. We investigated the role of Opa1 deficiency in ECs and vascular homeostasis using mice lacking the fusion protein Opa1 (heterozygous Opa1 ± mice). Endothelium-mediated dilatation was lower in Opa1 ± than in Opa1 +/+ mice, without change in vascular contractility in isolated arteries. Flow-mediated ECs alignment was reduced in Opa1± compared to Opa1 +/+ mice. We then investigated mitochondrial dynamics-related proteins expression level in ECs submitted to a disturbed shear stress (evidenced by eNOS down-regulation and endothelin-1 up-regulation) and observed a reduction in fusion protein Opa1 mRNA expression and an increase in fission protein Drp1 mRNA expression level. As shear stress determines atherogenesis in large arteries, we investigated mitochondrial dynamics-related proteins in various areas in the mouse aorta. In the area submitted to low shear stress, Opa1 mRNA expression was reduced and Drp1 mRNA expression was increased compared to other parts of the aorta submitted to higher shear stress. These observations led to investigate atherosclerosis in Opa1± mice. These mice, when crossed with LDLr-/- mice and fed high-fat diet, develop more atherosclerosis than Opa1 +/+ mice. Thus, reduced mitochondrial fusion altered endothelium-dependent functions and exacerbated plaque formation in atherosclerotic mice. And, in order to investigate the mechanism by which the ECs respond to shear stress, we are studying the effect of mitochondrial dynamic proteins on endothelial cells alignment and functions.

Whole cigarette smoke condensates induce ferroptosis in human bronchial epithelial cells

Cigarette smoke is responsible for many fatal pulmonary diseases, however, the toxic mechanism is still unclear. In this study, we first confirmed that whole cigarette smoke condensates (WCSC) contain hydrophilic elements, lipophilic and gaseous components. Then, we treated BEAS-2B cells, a normal human bronchial epithelial cell line, at dosages of 0.25, 0.5, and 1% for 24 h and explored the toxic mechanism. Cell viability decreased in a dose-dependent manner, and fission and fusion of mitochondria, damage of endoplasmic reticulume (ER) structures, and formation of autophagosome-like vacuoles were found in cells treated with 1% WCSC. Mitochondrial and ER volumes, lysosomal fluorescence intensity, LDH release, and intracellular ROS levels notably decreased at the highest doses compared with the control, whereas intracellular calcium ion and NO levels were significantly elevated accompanying G2/M phase arrest. Expression of an iron-binding nuclear protein-related gene (pirin) was the most up-regulated in the WCSC-treated cells with enhanced expression of antioxidant-related genes, whereas expression of carbonic anhydrase IX gene, a marker of tumor hypoxia, was the most down-regulated. Additionally, levels of apoptosis (BAX, Apaf-1, and cleavage of caspase-3 and PARP), autophagy (p62 and LC3B-II), ER stress (PERK, IRE-1a, Bip, and CHOP), antioxidant (SOD-1 and SOD-2), and MAPkinase activation (p-ERK, p-p38, and p-JNK)-related proteins were clearly enhanced following exposure to WCSC, whereas expression of several mitochondrial dynamics-related proteins was reduced with dose. Interestingly, expression of ferritin protein (light chain) was dramatically enhanced near the ER along with that of p62 protein. More importantly, the hypoxia inducible factor-1 pathway and ferroptosis were proposed among the 20 terms in KEGG pathway analysis, and secretion of IL-6 and IL-8, which are involved in hypoxia-induced inflammation, were clearly elevated with dose. Taken together, we suggest that WCSC may induce ferroptosis in bronchial epithelial cells via ER stress and disturbed homeostasis in mitochondrial dynamics caused by induction of hypoxia conditions.

Effects of Millimolar Steady-State Hydrogen Peroxide Exposure on Inflammatory and Redox Gene Expression in Immune Cells from Humans with Metabolic Syndrome.

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) can exert opposed effects depending on the dosage: low levels can be involved in signalling and adaptive processes, while higher levels can exert deleterious effects in cells and tissues. Our aim was to emulate a chronic ex vivo oxidative stress situation through a 2 h exposure of immune cells to sustained H2O2 produced by glucose oxidase (GOX), at high or low production rate, in order to determine dissimilar responses of peripheral blood mononuclear cells (PBMCs) and neutrophils on ROS and cytokine production, and mitochondrial dynamics-related proteins, pro/anti-inflammatory and anti-oxidant gene expression. Immune cells were obtained from subjects with metabolic syndrome. H2O2 at low concentrations can trigger a transient anti-inflammatory adiponectin secretion and reduced gene expression of toll-like receptors (TLRs) in PBMCs but may act as a stimulator of proinflammatory genes (IL6, IL8) and mitochondrial dynamics-related proteins (Mtf2, NRF2, Tfam). H2O2 at a high concentration enhances the expression of pro-inflammatory genes (TLR2 and IL1β) and diminishes the expression of mitochondrial dynamics-related proteins (Mtf1, Tfam) and antioxidant enzymes (Cu/Zn SOD) in PBMCs. The GOX treatments produce dissimilar changes in immune cells: Neutrophils were more resistant to H2O2 effects and exhibited a more constant response in terms of gene expression than PBMCs. We observe emerging roles of H2O2 in mitochondrial dynamics and redox and inflammation processes in immune cells.

Intensified mitophagy in skeletal muscle with aging is downregulated by PGC-1alpha overexpression in vivo

Mitochondrial dysfunction plays an important role in the etiology of age-related muscle atrophy known as sarcopenia. PGC-1α is positioned at the center of crosstalk in regulating mitochondrial quality control, but its role in mitophagy in aged skeletal muscle is currently unclear. The present study investigated the effects of aging and PGC-1α overexpression via in vivo DNA transfection on key mitophagy protein markers, as well as mitochondrial dynamics related proteins, metabolic function and antioxidant capacity in mouse muscle. C57BL/6J mice at the age of 2 mo (young, Y; N = 14) and 24 mo (old, O; N = 14) were transfected in vivo with either PGC-1α DNA (OE, N = 7) or GFP (N = 7) into the tibialis anterior (TA) muscle followed by electroporation. PINK1 and Parkin protein contents were 3.6 and 1.4-fold higher (P < 0.01), whereas mitochondrial ubiquitination (Ub) increased 1.5-fold (P < 0.05), in O vs. Y mice. PGC-1 OE suppressed PINK and Parkin protein levels by 50–60% (P < 0.01), and decreased Ub by 20% (P < 0.05) in old mice. Aging significantly increased the protein content of LC3II (30%, P < 0.05), p62 (42%, P < 0.05), RheB (5.5-fold, P < 0.01), Beclin-1 (3-fold, P < 0.01) and Mfn2 (~4-fold, P < 0.01) in the TA muscle. However, these age-related increases in mitophagy markers were attenuated by PGC-1α OE. Furthermore, aging dramatically increased Fis-1 protein content by 14-fold (P < 0.01), along with a severe reduction of citrate synthase activity (64%, P < 0.01) and cytochrome c oxidase subunit IV (COXIV) protein content (85%, P < 0.01). PGC-1α OE mitigated the age effects on Fis-1 and Drp-1 (P < 0.05). Moreover, PGC-1α OE enhanced mitochondrial oxidative function and antioxidant enzyme activities, and decreased lipid peroxidation and inner membrane damage found in old mice (P < 0.01). In summary, our data demonstrate that mitophagy protein expression in skeletal muscle was enhanced at old age driven possibly by increased mitochondrial dysfunction, damage, and fission. PGC-1α OE was effective in ameliorating mitochondrial deficits but did not restore muscle fiber atrophy.

Parkin is a disease modifier in the mutant SOD1 mouse model of ALS.

Mutant Cu/Zn superoxide dismutase (SOD1) causes mitochondrial alterations that contribute to motor neuron demise in amyotrophic lateral sclerosis (ALS). When mitochondria are damaged, cells activate mitochondria quality control (MQC) mechanisms leading to mitophagy. Here, we show that in the spinal cord of G93A mutant SOD1 transgenic mice (SOD1‐G93A mice), the autophagy receptor p62 is recruited to mitochondria and mitophagy is activated. Furthermore, the mitochondrial ubiquitin ligase Parkin and mitochondrial dynamics proteins, such as Miro1, and Mfn2, which are ubiquitinated by Parkin, and the mitochondrial biogenesis regulator PGC1α are depleted. Unexpectedly, Parkin genetic ablation delays disease progression and prolongs survival in SOD1‐G93A mice, as it slows down motor neuron loss and muscle denervation and attenuates the depletion of mitochondrial dynamics proteins and PGC1α. Our results indicate that Parkin is a disease modifier in ALS, because chronic Parkin‐mediated MQC activation depletes mitochondrial dynamics‐related proteins, inhibits mitochondrial biogenesis, and worsens mitochondrial dysfunction.

Haemin attenuates intermittent hypoxia-induced cardiac injury via inhibiting mitochondrial fission.

Obstructive sleep apnoea (OSA) characterized by intermittent hypoxia (IH) is closely associated with cardiovascular diseases. IH confers cardiac injury via accelerating cardiomyocyte apoptosis, whereas the underlying mechanism has remained largely enigmatic. This study aimed to explore the potential mechanisms involved in the IH‐induced cardiac damage performed with the IH‐exposed cell and animal models and to investigate the protective effects of haemin, a potent haeme oxygenase‐1 (HO‐1) activator, on the cardiac injury induced by IH. Neonatal rat cardiomyocyte (NRC) was treated with or without haemin before IH exposure. Eighteen male Sprague‐Dawley (SD) rats were randomized into three groups: control group, IH group (PBS, ip) and IH + haemin group (haemin, 4 mg/kg, ip). The cardiac function was determined by echocardiography. Mitochondrial fission was evaluated by Mitotracker staining. The mitochondrial dynamics‐related proteins (mitochondrial fusion protein, Mfn2; mitochondrial fission protein, Drp1) were determined by Western blot. The apoptosis of cardiomyocytes and heart sections was examined by TUNEL. IH regulated mitochondrial dynamics‐related proteins (decreased Mfn2 and increased Drp1 expressions, respectively), thereby leading to mitochondrial fragmentation and cell apoptosis in cardiomyocytes in vitro and in vivo, while haemin‐induced HO‐1 up‐regulation attenuated IH‐induced mitochondrial fragmentation and cell apoptosis. Moreover, IH resulted in left ventricular hypertrophy and impaired contractile function in vivo, while haemin ameliorated IH‐induced cardiac dysfunction. This study demonstrates that pharmacological activation of HO‐1 pathway protects against IH‐induced cardiac dysfunction and myocardial fibrosis through the inhibition of mitochondrial fission and cell apoptosis.

Mitochondrial Dynamics: Shaping Metabolic Adaptation.

Despite their classic bean-shaped depiction, mitochondria have very different aspects in each cell type. From long filamentous structures to punctuated small round organelles. These shapes can dynamically change in response to nutrients and in situations of metabolic disease. However, why do mitochondria adapt different shapes and how is this determined? In this review, we will aim to understand different visions on how metabolic cues influence mitochondrial shape and vice-versa. This response can be dramatically different between tissues and cells, as illustrated by a large array of genetically engineered mouse models reported to date. We will use these models to understand the role of different mitochondrial dynamics-related proteins and processes.

Determining the target protein localization in 3D using the combination of FIB-SEM and APEX2

Determining the cellular localization of proteins of interest at nanometer resolution is necessary for elucidating their functions. Besides super-resolution fluorescence microscopy, conventional electron microscopy (EM) combined with immunolabeling or clonable EM tags provides a unique approach to correlate protein localization information and cellular ultrastructural information. However, there are still rare cases of such correlation in three-dimensional (3D) spaces. Here, we developed an approach by combining the focus ion beam scanning electron microscopy (FIB-SEM) and a promising clonable EM tag APEX2 (an enhanced ascorbate peroxidase 2) to determine the target protein localization within 3D cellular ultrastructural context. We further utilized this approach to study the 3D localization of mitochondrial dynamics-related proteins (MiD49/51, Mff, Fis1, and Mfn2) in the cells where the target proteins were overexpressed. We found that all the target proteins were located at the surface of the mitochondrial outer membrane accompanying with mitochondrial clusters. Mid49/51, Mff, and hFis1 spread widely around the mitochondrial surface while Mfn2 only exists at the contact sites.

Insulin-stimulated lipid accumulation is inhibited by ROS-scavenging chemicals, but not by the Drp1 inhibitor Mdivi-1.

Adipocyte differentiation is regulated by intracellular reactive oxygen species (ROS) generation and mitochondrial fission and fusion processes. However, the correlation between intracellular ROS generation and mitochondrial remodeling during adipocyte differentiation is still unknown. Here, we investigated the effect on adipocyte differentiation of 3T3-L1 cells of intracellular ROS inhibition using N-acetyl cysteine (Nac) and Mito-TEMPO and of mitochondrial fission inhibition using Mdivi-1. Differentiated 3T3-L1 adipocytes displayed an increase in mitochondrial fission, ROS generation, and the expression of adipogenic and mitochondrial dynamics-related proteins. ROS scavenger (Nac or Mito-TEMPO) treatment inhibited ROS production, lipid accumulation, the expression of adipogenic and mitochondrial dynamics-related proteins, and mitochondrial fission during adipogenesis of 3T3-L1 cells. On the other hand, treatment with the mitochondrial fission inhibitor Mdivi-1 inhibited mitochondrial fission but did not inhibit ROS production, lipid accumulation, or the expression of adipogenic and mitochondrial dynamics-related proteins, with the exception of phosphorylated Drp1 (Ser616), in differentiated 3T3-L1 adipocytes. The inhibition of mitochondrial fission did not affect adipocyte differentiation, while intracellular ROS production decreased in parallel with inhibition of adipocyte differentiation. Therefore, our results indicated that ROS are an essential regulator of adipocyte differentiation in 3T3-L1 cells.

Peroxisome proliferator-activated receptor (PPAR) γ and PPARα agonists modulate mitochondrial fusion-fission dynamics: relevance to reactive oxygen species (ROS)-related neurodegenerative disorders?

Recent studies showed that the activation of the retinoid X receptor, which dimerizes with peroxisome proliferator-activated receptors (PPARs), leads to an enhanced clearance of Aβ from the brain of transgenic mice model of Alzheimer’s disease (AD), because an increased expression of apolipoprotein E and it main transporters. However, the effects observed must involve additional underlying mechanisms that have not been yet explored. Several studies conducted in our laboratory suggest that part of the effects observed for the PPARs agonist might involves mitochondrial function and, particularly, mitochondrial dynamics. In the present study we assessed the effects of oxidative stress challenge on mitochondrial morphology and mitochondrial dynamics-related proteins in hippocampal neurons. Using immunofluorescence, we evaluated the PPARγ co-activator 1α (PGC-1α), dynamin related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and mitochondrial length, in order to determine if PPARs agonist pre-treatment is able to protect mitochondrial population from hippocampal neurons through modulation of the mitochondrial fusion-fission events. Our results suggest that both a PPARγ agonist (ciglitazone) and a PPARα agonist (WY 14.643) are able to protect neurons by modulating mitochondrial fusion and fission, leading to a better response of neurons to oxidative stress, suggesting that a PPAR based therapy could acts simultaneously in different cellular components. Additionally, our results suggest that PGC-1α and mitochondrial dynamics should be further studied in future therapy research oriented to ameliorate neurodegenerative disorders, such as AD.