Lutein upregulates the PGC-1α, NRF1, and TFAM expression by AMPK activation and downregulates ROS to maintain mtDNA integrity and mitochondrial biogenesis in hyperglycemic ARPE-19 cells and rat retina.

Hyperglycemia (HG) affects cellular organelle including mitochondrion in retina that diminishes mitochondrial biogenesis by downregulation of nuclear transcription factors peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1α) and mitochondrial transcription factor A (TFAM). Mitochondrial dysfunction has been linked to diabetic retinopathy (DR). Carotenoids reported to modulate mitochondrial biogenesis in HG. Aim of the study was to explore the role of lutein, oxidized lutein (purified upon UV oxidation of lutein) and drug metformin, on mitochondrial biogenesis in HG-induced ARPE-19 cells and rat retina. Results showed higher uptake of lutein and oxidized lutein in ARPE-19 cells and rat retina of HG group than the control groups. Further, lutein and oxidized lutein augmented the AMPK phosphorylation and activation of mitochondrion signaling molecule TFAM (protein expression) and mRNA expression of PGC-1α, TFAM, and nuclear respiratory factor 1 (responsible for mitochondria biogenesis) along with lowered reactive oxygen species in HG compared with control and metformin groups. Higher mRNA expression of nicotinamide adenine dinucleotide dehydrogenase subunits mt-ND1, mt-ND4, mt-ND6, and cytochrome C that aid maintenance of mtDNA integrity was also evidenced. To conclude, lutein and oxidized lutein found to upsurge mitochondrial biogenesis in ARPE-19 cells and rat retina under HG, which may be due to upregulation of AMPK phosphorylation. Finally, lutein and oxidized lutein may provide a therapeutic basis to ameliorate HG-induced DR.

Nanjaiah H ，Vallikannan B 《-》

Enhanced phosphorylation of AMPK by lutein and oxidised lutein that lead to mitochondrial biogenesis in hyperglycemic HepG2 cells.

The stimulation of adenosine monophosphate-activated protein kinase (AMPK) is a prime target to decrease the hyperglycemic condition, hence it is a lutein (L) and oxidised lutein (OXL) is a target molecule for the treatment of type II diabetes. In the current study, a plausible interaction of L and OXL with AMPK was investigated by molecular docking. In addition, the effect of L and OXL for the activation of AMPK that triggers the downstream regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), TFAM expression, mitochondrial DNA (mtDNA), mitochondrial biogenesis and superoxide dismutase 2 (SOD2) in high glucose treated HepG2 cells were investigated by quantitative polymerase chain reaction and Western blot analysis. Molecular docking reveals higher binding affinity of L (ΔG = -6.3 kcal/mol) and OXL (ΔG = -15.5 kcal/mol) with AMPK, compared with metformin (ΔG = -5.0 kcal/mol). The phosphorylation of AMPK increased by 1.3- and 1.5-fold with L and OXL treatment, respectively, in high glucose induced HepG2 cells. The activation of PGC-1α is significant (P < 0.05) in OXL group than L. Similarly, TFAM expression is increased with L and OXL compared with the high glucose group. Further increase in SOD2 and mtDNA, confirms the efficacy of L and OXL in restoring the mitochondrial biogenesis in high glucose induced cells through AMPK, PGC-1α, and TFAM.

Nanjaiah H ，Vallikannan B 《-》

Resistin destroys mitochondrial biogenesis by inhibiting the PGC-1α/ NRF1/TFAM signaling pathway.

Mitochondrial biogenesis deficits in neuronal cells are associated with the pathological progression of neurodegenerative diseases. Resistin, a secretory adipocytokine, possesses multiple physiological functions in diverse cells and tissues. However, the effects of resistin on mitochondrial biogenesis in neuronal cells are still elusive. In the current study, we found that resistin caused a sustainable decrease in mitochondrial contents, including mitochondrial DNA/nuclear DNA ratio (mtDNA/nDNA), mitochondrial mass, cytochrome b protein expression, and cytochrome c oxidase activity, which were correlated with "loss of mitochondrial function" including reduced mitochondrial respiration rate and ATP production in human SH-SY5Y neuronal cells. Indeed, resistin treatment destroyed the expression of peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis, as well as its downstream target genes including nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Notably, overexpression of PGC-1α could completely rescue mitochondrial biogenesis and mitochondrial deficits induced by resistin. Mechanistically, inhibition of 5'-adenosine monophosphate-activated protein kinase (AMPK) was shown to mediate the inhibitory effects of resistin on mitochondrial biogenesis.

Chen Z ，Tao S ，Li X ，Yao Q ... -  《-》

Salicylates promote mitochondrial biogenesis by regulating the expression of PGC-1α in murine 3T3-L1 pre-adipocytes.

Mitochondrial dysfunction has been associated with insulin resistance and diabetes. Decreased mitochondrial density and mitochondrial copy numbers have been found in insulin-resistant individuals. Restoration of the number of mitochondria and normal mitochondrial function has become an important therapeutic target of diabetes. Salicylate, the main active ingredient in aspirin, has been in medicinal use since ancient times. Little information regarding the effects of salicylate on mitochondrial function has been reported. In this study, we assessed the effects of salicylate on the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) signaling pathway and mitochondrial biogenesis in pre-adipocytes. Our findings demonstrate that treatment with salicylate promoted the expression of PGC-1α and its downstream targets nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Importantly, salicylate treatment significantly increased the number of mDNA, citrate synthase activity, expression of respiratory chain complex I, and mitochondrial mass, which were suppressed by the specific AMPK inhibitor Compound C. Indeed, salicylate treatment induced the phosphorylation of AMPK, which was involved in the induction of PGC-1α, NRF1, and TFAM. Importantly, inhibition of PGC-1α expression using PGC-1α small RNA interference abolished the effects of salicylate on mitochondrial biogenesis. These results suggest that salicylate has a potential therapeutic capacity against mitochondrial dysfunction in diabetes.

Yan Y ，Yang X ，Zhao T ，Zou Y ，Li R ，Xu Y ... -  《-》

Propofol induces impairment of mitochondrial biogenesis through inhibiting the expression of peroxisome proliferator-activated receptor-γ coactivator-1α.

Propofol is a commonly used general anesthetic in patient care. Recent studies have shown that propofol has neurological side effects especially in young children, which raises a concern regarding the safety of its use. We explored the effects of the molecular mechanism of propofol on neuronal mitochondrial function in SH-SY5Y cells. Our results demonstrate that clinically relevant doses of propofol reduce the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in a dose- and time-dependent manner. At a concentration of 2%, propofol suppresses the mitochondrial regulator nuclear respiratory factor 1 and mitochondrial transcription factor A and impairs neuronal mitochondrial biogenesis. These impairments involve reduction of mitochondrial mass and reduction of the ratio of mitochondrial to nuclear DNA as well as reduction of cytochrome C oxidase activity. Propofol treatment reduces intracellular adenosine triphosphate (ATP) production, the mitochondrial respiratory rate, and increases mitochondrial reactive oxygen species production, implying that it disturbs neuronal mitochondrial function. Overexpression of PGC-1α rescued propofol-induced reduced mitochondrial mass, ATP production, and respiratory rate, indicating that PGC-1α is the mediator of the effect of propofol on mitochondrial function. Finally, we demonstrate that propofol suppresses PGC-1α by inhibiting cAMP-response element binding protein (CREB) activation and promoting PKA RI expression, and the addition of cyclic adenosine monophosphate rescues propofol-mediated reduced PGC-1α. In conclusion, PGC-1α is the central mediator of propofol-induced impairment of mitochondrial biogenesis and neuronal mitochondrial dysfunction. Our study demonstrates the molecular mechanism behind propofol-induced neurotoxicity and provides valuable information regarding its side effects in clinical practice.

Qin J ，Li Y ，Wang K 《-》