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Role of microRNA-130b in placental PGC-1?/TFAM mitochondrial biogenesis pathway.

ABSTRACT: Diabetes during pregnancy is associated with abnormal placenta mitochondrial function and increased oxidative stress, which affect fetal development and offspring long-term health. Peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) is a master regulator of mitochondrial biogenesis and energy metabolism. The molecular mechanisms underlying the regulation of PGC-1? in placenta in the context of diabetes remain unclear. The present study examined the role of microRNA 130b (miR-130b-3p) in regulating PGC-1? expression and oxidative stress in a placental trophoblastic cell line (BeWo). Prolonged exposure of BeWo cells to high glucose mimicking hyperglycemia resulted in decreased protein abundance of PGC-1? and its downstream factor, mitochondrial transcription factor A (TFAM). High glucose treatment increased the expression of miR-130b-3p in BeWo cells, as well as exosomal secretion of miR-130b-3p. Transfection of BeWo cells with miR-130b-3p mimic reduced the abundance of PGC-1?, whereas inhibition of miR-130b-3p increased PGC-1? expression in response to high glucose, suggesting a role for miR-130b-3p in mediating high glucose-induced down regulation of PGC-1? expression. In addition, miR-130b-3p anti-sense inhibitor increased TFAM expression and reduced 4-hydroxynonenal (4-HNE)-induced production of reactive oxygen species (ROS). Taken together, these findings reveal that miR-130b-3p down-regulates PGC-1? expression in placental trophoblasts, and inhibition of miR-130b-3p appears to improve mitochondrial biogenesis signaling and protect placental trophoblast cells from oxidative stress.

SUBMITTER: Jiang S

PROVIDER: S-EPMC5522006 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Role of microRNA-130b in placental PGC-1α/TFAM mitochondrial biogenesis pathway.

Jiang Shaoning S Teague April M AM Tryggestad Jeanie B JB Chernausek Steven D SD

Biochemical and biophysical research communications 20170419 3

Diabetes during pregnancy is associated with abnormal placenta mitochondrial function and increased oxidative stress, which affect fetal development and offspring long-term health. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis and energy metabolism. The molecular mechanisms underlying the regulation of PGC-1α in placenta in the context of diabetes remain unclear. The present study examined the role of microRNA 130b (miR-130 ...[more]

PMID: 28433632

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Project description:The use of mesenchymal stem cells (MSCs) has become a new strategy for treating diabetic kidney disease (DKD). However, the role of placenta derived mesenchymal stem cells (P-MSCs) in DKD remains unclear. This study aims to investigate the therapeutic application and molecular mechanism of P-MSCs on DKD from the perspective of podocyte injury and PINK1/Parkin-mediated mitophagy at the animal, cellular, and molecular levels. Western blotting, reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to detect the expression of podocyte injury-related markers and mitophagy-related markers, SIRT1, PGC-1α, and TFAM. Knockdown, overexpression, and rescue experiments were performed to verify the underlying mechanism of P-MSCs in DKD. Mitochondrial function was detected by flow cytometry. The structure of autophagosomes and mitochondria were observed by electron microscopy. Furthermore, we constructed a streptozotocin-induced DKD rat model and injected P-MSCs into DKD rats. Results showed that as compared with the control group, exposing podocytes to high-glucose conditions aggravated podocyte injury, represented by a decreased expression of Podocin along with increased expression of Desmin, and inhibited PINK1/Parkin-mediated mitophagy, manifested as a decreased expression of Beclin1, the LC3II/LC3I ratio, Parkin, and PINK1 associated with an increased expression of P62. Importantly, these indicators were reversed by P-MSCs. In addition, P-MSCs protected the structure and function of autophagosomes and mitochondria. P-MSCs increased mitochondrial membrane potential and ATP content and decreased the accumulation of reactive oxygen species. Mechanistically, P-MSCs alleviated podocyte injury and mitophagy inhibition by enhancing the expression of the SIRT1-PGC-1α-TFAM pathway. Finally, we injected P-MSCs into streptozotocin-induced DKD rats. The results revealed that the application of P-MSCs largely reversed the markers related to podocyte injury and mitophagy and significantly increased the expression of SIRT1, PGC-1α, and TFAM compared with the DKD group. In conclusion, P-MSCs ameliorated podocyte injury and PINK1/Parkin-mediated mitophagy inhibition in DKD by activating the SIRT1-PGC-1α-TFAM pathway.

Dataset Information

Role of microRNA-130b in placental PGC-1?/TFAM mitochondrial biogenesis pathway.

Publications

Role of microRNA-130b in placental PGC-1α/TFAM mitochondrial biogenesis pathway.

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