Energy stress modulation of AMPK/FoxO3 signaling inhibits mitochondria-associated ferroptosis.

Cancer cells and ischemic diseases exhibit unique metabolic responses and adaptations to energy stress. Forkhead box O 3a (FoxO3a) is a transcription factor that plays an important role in cell metabolism, mitochondrial dysfunction and oxidative stress response. Although the AMP-activated protein kinase (AMPK)/FoxO3a signaling pathway plays a pivotal role in maintaining energy homeostasis under conditions of energy stress, the role of AMPK/FoxO3a signaling in mitochondria-associated ferroptosis has not yet been fully elucidated. We show that glucose starvation induced AMPK/FoxO3a activation and inhibited ferroptosis induced by erastin. Inhibition of AMPK or loss of FoxO3a in cancer cells under the glucose starvation condition can sensitize these cells to ferroptosis. Glucose deprivation inhibited mitochondria-related gene expression, reduced mitochondrial DNA(mtDNA) copy number, decreased expression of mitochondrial proteins and lowered the levels of respiratory complexes by inducing FoxO3a. Loss of FoxO3a promoted mitochondrial membrane potential hyperpolarization, oxygen consumption, lipid peroxide accumulation and abolished the protective effects of energy stress on ferroptosis in vitro. In addition, we identified a FDA-approved antipsychotic agent, the potent FoxO3a agonist trifluoperazine, which largely reduced ferroptosis-associated cerebral ischemia-reperfusion (CIR) injuries in rats through AMPK/FoxO3a/HIF-1α signaling and mitochondria-dependent mechanisms. We found that FoxO3a binds to the promoters of SLC7A11 and reduces CIR-mediated glutamate excitotoxicity through inhibiting the expression of SLC7A11. Collectively, these results suggest that energy stress modulation of AMPK/FoxO3a signaling regulates mitochondrial activity and alters the ferroptosis response. The regulation of FoxO3a by AMPK may play a crucial role in mitochondrial gene expression that controls energy balance and confers resistance to mitochondria-associated ferroptosis and CIR injuries.

Role of omentin-1 in susceptibility to anxiety and depression like behaviors.

Neuro-inflammation and blood-brain barrier (BBB) dysfunction are associated with depression. Evidence shows that adipokines enter the brain from the circulation, which regulates depressive behaviors. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about its role in neuro-inflammation and mood-relevant behavior. Our results showed omentin-1 knockout mice (Omentin-1-/-) increased susceptibility to anxiety and depressive-like behaviors, which are associated with abnormalities of cerebral blood flow (CBF) and impaired BBB permeability. Moreover, omentin-1 depletion significantly increased hippocampal pro-inflammatory cytokines (IL-1ß, TNFα, IL-6), caused microglial activation, inhibited hippocampus neurogenesis, and resulted in autophagy impairment by dysregulating ATG genes. Omentin-1 deficiency also sensitized mice to the behavioral changes induced by lipopolysaccharide (LPS), suggesting that omentin-1 could rescue neuro-inflammation by acting as an anti-depressant. Our in vitro microglia cell culture data confirmed that recombinant omentin-1 suppresses microglial activation and pro-inflammatory cytokine expression induced by LPS. Our study suggests that omentin-1 can be used as a promising therapeutic agent for the prevention or treatment of depression by providing a barrier-promoting effect and an endogenous anti-inflammatory balance to downregulate the proinflammatory cytokines.

FoxO3a cooperates with RUNX1 to promote chondrogenesis and terminal hypertrophic of the chondrogenic progenitor cells.

FoxO transcription factors (FoxOs) have recently been shown to protect against chondrocyte dysfunction and modulate cartilage homeostasis in osteoarthritis. The mechanism underlying of FoxOs regulate chondrocyte differentiation remains unknown. Runt related transcription factor 1 (RUNX1) mediated both chondrocyte and osteoblast differentiation. Our data showed that FoxO3a and RUNX1 are co-expressed in ATDC5 cells and undifferentiated mesenchyme cells and have similar high levels in chondrocytes undergoing transition from proliferation to hypertrophy. Overexpression of FoxO3a in ATDC5 cells or mouse mesenchymal cells resulted in a potent induction of the chondrocyte differentiation markers. Knockdown FoxO3a or RUNX1 potently inhibits the expressions of chondrocyte differentiation markers, including Sox9, Aggrecan, Col2, and hypertrophic chondrocyte markers including RUNX2, ColX, MMP13 and ADAMTs-5 in ATDC5 cells. Co-immunoprecipitation showed that FoxO3a binds the transcriptional regulator RUNX1. Immunohistochemistry showed that FoxO3a and RUNX1 are highly co-expressed in the proliferative chondrocytes of the growth plates in the hind limbs of newborn mice. Collectively, we revealed that FoxO3a cooperated with RUNX1 promoted chondrocyte differentiation through enhancing both early chondrogenesis and terminal hypertrophic of the chondrogenic progenitor cells, indicating FoxO3a interacting with RUNX1 may be a therapeutic target for the treatment of osteoarthritis and other bone diseases.