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 《-》

Overexpression of human selenoprotein H in neuronal cells enhances mitochondrial biogenesis and function through activation of protein kinase A, protein kinase B, and cyclic adenosine monophosphate response element-binding protein pathway.

Mitochondrial biogenesis is activated by nuclear encoded transcription co-activator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which is regulated by several upstream factors including protein kinase A and Akt/protein kinase B. We have previously shown that selenoprotein H enhances the levels of nuclear regulators for mitochondrial biogenesis, increases mitochondrial mass and improves mitochondrial respiratory rate, under physiological condition. Furthermore, overexpression of selenoprotein H protects neuronal HT22 cells from ultraviolet B irradiation-induced cell damage by lowering reactive oxygen species production, and inhibiting activation of caspase-3 and -9, as well as p53. The objective of this study is to identify the cell signaling pathways by which selenoprotein H initiates mitochondrial biogenesis. We first confirmed our previous observation that selenoprotein H transfected HT22 cells increased the protein levels of nuclear-encoded mitochondrial biogenesis factors, peroxisome proliferator-activated receptor γ coactivator-1α, nuclear respiratory factor 1 and mitochondrial transcription factor A. We then observed that total and phosphorylation of protein kinase A, Akt/protein kinase B and cyclic adenosine monophosphate response element-binding protein (CREB) were significantly increased in selenoprotein H transfected cells compared to vector transfected HT22 cells. To verify whether the observed stimulating effects on mitochondrial biogenesis pathways are caused by selenoprotein H and mediated through CREB, we knocked down selenoprotein H mRNA level using siRNA and inhibited CREB with napthol AS-E phosphate in selenoprotein H transfected cells and repeated the measurements of the aforementioned biomarkers. Our results revealed that silencing of selenoprotein H not only decreased the protein levels of PGC-1α, nuclear respiratory factor 1 and mitochondrial transcription factor A, but also decreased the total and phosphorylation levels of protein kinase A, protein kinase B, and CREB. Similarly, CREB inhibition reduced CREB activation and PGC-1α protein levels in selenoprotein H transfected cells. Moreover, selenoprotein H transfection increased the activity of mitochondrial complexes and prevented the ultraviolet B induced fall of mitochondrial membrane potential. We conclude that the effects of selenoprotein H on mitochondrial biogenesis and mitochondrial function are probably mediated through protein kinase A-CREB-PGC-1α and Akt/protein kinase B-CREB-PGC-1α pathways.

Mehta SL ，Mendelev N ，Kumari S ，Andy Li P ... -  《-》

Activation of TGR5 promotes mitochondrial biogenesis in human aortic endothelial cells.

Impairment of mitochondrial biogenesis has been associated with vascular pathophysiology. The G-protein-coupled receptor (TGR5) is an important mediator of bile acid signaling and glucose metabolism. However, the effects of TGR5 on mitochondrial biogenesis in endothelial cells remain elusive. In this study, we found that activation of TGR5 using its specific agonist taurolithocholic acid (TLCA) promoted the expression of PGC-1α, a master regulator of mitochondrial biogenesis in human aortic endothelial cells (HAECs). Additionally, activation of TGR5 increased the expression of PGC-1α target genes, such as NRF1 and TFAM. Indeed, we found that TLCA treatment promoted mitochondrial biogenesis by increasing mitochondrial mass, mitochondrial-to-nuclear DNA (mtDNA/nDNA), COX-Ⅰ expression, and cytochrome c oxidase activity in HAECs. Notably, our results displayed that activation of TGR5 resulted in a functional gain in mitochondria by increasing the rate of respiration and ATP production. Mechanistically, we found that TLCA treatment activated the transcriptional factor CREB by inducing the phosphorylation of CREB at Ser133. Using the PKA/CREB inhibitor H89 abolished the effects of TLCA on PGC-1α, NRF1 and TFAM expression as well as the increase in mtDNA/nDNA and ATP production. These findings suggest that activation of TGR5 promoted mitochondrial biogenesis in endothelial cells, which is mediated by the CREB/PGC-1α signaling pathway.

Zhao LJ ，Zhang SF 《-》

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 ... -  《-》

Ropivacaine impairs mitochondrial biogenesis by reducing PGC-1α.

Ropivacaine is one of the commonly used local anesthetics in medical and dental care. However, preclinical and observational studies indicate that ropivacaine could have substantial side effects including neurotoxicity, which has raised concern regarding the safety of this drug. In the present study, we investigated the effects of clinically relevant doses of ropivacaine on mitochondrial biogenesis and function in neuronal cells. Our data indicate that exposure to ropivacaine leads to reduced expression of the major mitochondrial regulator PGC-1α and its downstream transcription factors NRF1 and TFAM. Ropivacaine treatment induces impairment of mitochondrial biogenesis by reducing mitochondrial mass, the ratio of mtDNA to nDNA (mtDNA/nDNA), cytochrome C oxidase activity, and COX-1 expression. Additionally, treatment with ropivacaine causes "loss of mitochondrial function" by impairing the mitochondrial respiratory rate and ATP production. Mechanistically, the reduction of PGC-1α caused by ropivacaine exposure requires inactivation of CREB, while re-introduction of PGC-1α completely rescues ropivacaine-induced mitochondrial abnormalities. In summary, our results provide supporting evidence that mitochondrial impairment is a key event in ropivacaine-mediated neurotoxicity, and the reduction of PGC-1α and its downstream signals are likely the molecular mechanism behind its cellular toxicity.

Niu Z ，Tang J ，Ren Y ，Feng W ... -  《-》