Biology subjects

Eliseev, R. A.

Publications and source records attributed to Eliseev, R. A..

3 recordsLinked to original sources

bioRxiv2021

Transcriptional regulation of cyclophilin D by BMP/SMAD signaling and its role in osteogenic differentiation

Cyclophilin D (CypD) promotes opening of the mitochondrial permeability transition pore (MPTP) which plays a key role in both cell physiology and pathology. It is, therefore beneficial for cells to tightly regulate CypD and MPTP but little is known about such regulation. We have reported before that CypD is downregulated and MPTP deactivated during differentiation in various tissues. Herein, we identify BMP/Smad signaling, a major driver of differentiation, as a transcriptional repressor of the CypD gene, Ppif. Using osteogenic induction of mesenchymal lineage cells as a model of BMP/Smad-dependent differentiation, we show that CypD is in fact transcriptionally repressed during this process. The importance of such CypD downregulation is evidenced by the negative effect of CypD rescue via gain-of-function on osteogenesis both in vitro and in vivo. In sum, we characterized BMP/Smad signaling as a regulator of CypD expression and elucidated the role of CypD downregulation during cell differentiation.

cell biology↗

bioRxiv2020

Activation of mitochondria is an acute Akt-dependent response during osteogenic differentiation

Osteogenic differentiation, the process by which bone marrow mesenchymal stem/stromal (a.k.a. skeletal stem) cells and osteoprogenitors form osteoblasts, is a critical event for bone formation during development, fracture repair, and tissue maintenance. Extra- and intracellular signaling pathways triggering osteogenic differentiation are relatively well known; however, the ensuing change in cell energy metabolism is less clearly defined. Here we tested the effect of osteogenic media containing ascorbate and β-glycerol phosphate, or various osteogenic hormones and growth factors on energy metabolism in long bone (ST2)- and calvarial bone (MC3T3-E1)-derived osteoprogenitors. We show that osteogenic media, and differentiation factors, Wnt3a and BMP2, stimulate mitochondrial oxidative phosphorylation (OxPhos) with little effect on glycolysis. The activation of OxPhos occurs acutely, suggesting a metabolic signaling change rather than protein expression change. To this end, we found that the observed mitochondrial activation is Akt-dependent. Akt is activated by osteogenic media, Wnt3a, and BMP2, leading to increased phosphorylation of various mitochondrial Akt targets, a phenomenon known to stimulate OxPhos. In sum, our data provide comprehensive analysis of cellular bioenergetics during osteoinduction in cells of two different origins (mesenchyme vs neural crest) and identify Wnt3a and BMP2 as physiological stimulators of mitochondrial respiration via Akt activation.The abbreviations used areAAAntimycin AALPAlkaline phosphataseBMP2Bone Morphogenic Protein 2CVCrystal ViolateECARExtracellular Acidification RateFCCPCarbonyl cyanide 4-(trifluoromethoxy)phenylhydrazoneOBMOsteoblastic media a.k.a. Ascorbic acid and beta-gycero phosphateOBsOsteoblastsOCROxygen Consumption RateOligoOligomycinOxPhosOxidative PhosphorylationROSReactive Oxygen SpeciesROTRotenoneWnt3aWingless protein 3aView Full Text

developmental biology↗

bioRxiv2019

Inhibition of the mitochondrial permeability transition exerts sex-specific stimulatory effect on fracture repair

Bone fracture is accompanied by mechanical stresses and inflammation - conditions that impair mitochondria via the phenomenon of permeability transition. This phenomenon occurs due to opening of the mitochondrial permeability transition pore (MPTP) promoted by cyclophilin D (CypD). MPTP opening exacerbates inflammation and cell death and, thus can disrupt fracture repair. Here we tested a hypothesis that protecting mitochondria from MPTP opening via inhibition of CypD improves fracture repair. Our data indicate that osteoblast activity, bone formation, and biomechanical properties of repaired bones were significantly increased in CypD knock-out mice when compared to controls during fracture repair. These effects were observed in male but not female mice, thus showing sexual dimorphism. Pharmacological inhibition of CypD with NIM811 in male mice also stimulated fracture repair. In addition, CypD knock-out or pharmacological inhibition produced pro-osteogenic effect in isolated bone marrow osteoprogenitors. This in vitro effect was associated with higher mitochondrial respiration and increased {beta}-catenin activity regulated by mitochondria-dependent acetylation. Our findings implicate a sex-specific role of MPTP in bone fracture and suggest CypD inhibition as a modality to promote fracture repair.

biochemistry↗