AKT-GSK3βSignaling Pathway Regulates Mitochondrial Dysfunction-Associated OPA1 Cleavage Contributing to Osteoblast Apoptosis: Preventative Effects of Hydroxytyrosol

Abstract

Oxidative stress (OS) induces osteoblast apoptosis, which plays a crucial role in the initiation and progression of osteoporosis. Although OS is closely associated with mitochondrial dysfunction, detailed mitochondrial mechanisms underlying OS-induced osteoblast apoptosis have not been thoroughly elucidated to date. In the present study, we found that mitochondrial abnormalities largely contributed to OS-induced osteoblast apoptosis, as evidenced by enhanced production of mitochondrial reactive oxygen species; considerable reduction in mitochondrial respiratory chain complex activity, mitochondrial membrane potential, and adenosine triphosphate production; abnormality in mitochondrial morphology; and alteration of mitochondrial dynamics. These mitochondrial abnormalities were primarily mediated by an imbalance in mitochondrial fusion and fission through a protein kinase B- (AKT-) glycogen synthase kinase 3β- (GSK3β-) optic atrophy 1- (OPA1-) dependent mechanism. Hydroxytyrosol (3,4-dihydroxyphenylethanol (HT)), an important compound in virgin olive oil, significantly prevented OS-induced osteoblast apoptosis. Specifically, HT inhibited OS-induced mitochondrial dysfunction by decreasing OPA1 cleavage and by increasing AKT and GSK3β phosphorylation. Together, our results indicate that the AKT-GSK3β signaling pathway regulates mitochondrial dysfunction-associated OPA1 cleavage, which may contribute to OS-induced osteoblast apoptosis. Moreover, our results suggest that HT could be an effective nutrient for preventing osteoporosis development.

The Effects of PK11195 and Protoporphyrin IX Can Modulate Chronic Alcohol Intoxication in Rat Liver Mitochondria under the Opening of the Mitochondrial Permeability Transition Pore

“…Akt, a serine/threonine protein kinase, is a key regulator of cell proliferation and survival. Akt is rapidly activated in response to oxidative stress and thus phosphorylates GSK-3β at Ser9 [53]. Here, we demonstrated an increase in the level of Akt phosphorylation in the Ethanol RLM compared to the Control RLM, and in turn, a decrease in GSK-3β phosphorylation.…”

Carbenoxolon Is Capable to Regulate the Mitochondrial Permeability Transition Pore Opening in Chronic Alcohol Intoxication

“…It was shown also that the ratio of pGSK-3β/GSK-3β correlates with the threshold Ca 2+ concentration needed to induce mPTP opening in mitochondria from rat cardiomyocytes [ 67 ]. GSK-3β is phosphorylated by a serine/threonine protein kinase, Akt [ 68 ], protein kinase A or ribosomal s6 kinase [ 69 , 70 ]. The phosphorylation of GSK-3β leads to its inactivation [ 71 ].…”

MicroRNA‑142 protects MC3T3‑E1 cells against high glucose‑induced apoptosis by targeting β‑catenin

“…Recently, increased osteoblast apoptosis has been demonstrated to serve an important role in bone development and maintenance, and osteoporosis development (13,14). Research has highlighted the roles of miRs as the critical mediators of osteogenic development.…”