METTL14 promotes apoptosis of spinal cord neurons by inducing EEF1A2 m6A methylation in spinal cord injury

Abstract

Spinal cord injury (SCI) is a devastating traumatic condition. METTL14-mediated m6A modification is associated with SCI. This study was intended to investigate the functional mechanism of RNA methyltransferase METTL14 in spinal cord neuron apoptosis during SCI. The SCI rat model was established, followed by evaluation of pathological conditions, apoptosis, and viability of spinal cord neurons. The neuronal function of primary cultured spinal motoneurons of rats was assessed after hypoxia/reoxygenation treatment. Expressions of EEF1A2, Akt/mTOR pathway-related proteins, inflammatory cytokines, and apoptosis-related proteins were detected. EEF1A2 was weakly expressed and Akt/mTOR pathway was inhibited in SCI rat models. Hypoxia/Reoxygenation decreased the viability of spinal cord neurons, promoted LDH release and neuronal apoptosis. EEF1A2 overexpression promoted the viability of spinal cord neurons, inhibited neuronal apoptosis, and decreased inflammatory cytokine levels. Silencing METTL14 inhibited m6A modification of EEF1A2 and increased EEF1A2 expression while METTL14 overexpression showed reverse results. EEF1A2 overexpression promoted viability and inhibited apoptosis of spinal cord neurons and inflammation by activating the Akt/mTOR pathway. In conclusion, silencing METTL14 repressed apoptosis of spinal cord neurons and attenuated SCI by inhibiting m6A modification of EEF1A2 and activating the Akt/mTOR pathway.

N6-methyladenosine modification: A potential regulatory mechanism in spinal cord injury

“…These findings indicate that METTL14 is involved in the regulation of axons after SCI (Wang et al, 2021). And another study found that METTL14 catalyzes the m6A methylation of EEF1A2 mRNA (Gao et al, 2022). Knockdown of mettl14 can increase the level of EEF1A2, and the opposite occurs after mettl14 overexpression (Gao et al, 2022).…”

“…More importantly, further experiments also showed that overexpression of Mettl14 can induce apoptosis in vitro, as Mettl14 can promote the conversion of pri-miR-375 to miR-375, which is related to apoptosis and inhibits neural recovery (Wang et al, 2021). In addition, increased expression of METTL14 during SCI mediates the m6A modification of EEF1A2, which accelerates neuronal degeneration through the apoptotic pathway and impairs recovery after injury (Gao et al, 2022). EEF1A2 expression is reduced after SCI, while silencing of mettl14 increases EEF1A2 levels, decreases inflammatory cytokine production, and reduces neuronal degeneration in the spinal cord (Gao et al, 2022).…”

“…Recent studies have also reported that after SCI, the levels of m6A as well as writers, such as mettl3 and mettl14, in tissues rise dramatically and specific knockout of methylase can alleviate the severity of SCI (Wang et al, 2021;Xing et al, 2021;Gao et al, 2022). This indicates that dynamic m6A modification has a strong potential to regulate the injury mechanism after SCI and influencing functional recovery.…”

“…In addition, increased expression of METTL14 during SCI mediates the m6A modification of EEF1A2, which accelerates neuronal degeneration through the apoptotic pathway and impairs recovery after injury (Gao et al, 2022). EEF1A2 expression is reduced after SCI, while silencing of mettl14 increases EEF1A2 levels, decreases inflammatory cytokine production, and reduces neuronal degeneration in the spinal cord (Gao et al, 2022).…”

“…Recent studies have found that after SCI, the overall m6A level in the lesion site is increased, and the content of related regulatory factors, such as METTL3 and METTL14, are increased (Xing et al, 2021;Wang et al, 2021;Gao et al, 2022). Furthermore, it was discovered that the specific knockout of mettl14 helps functional recovery after SCI and reduces neuronal apoptosis (Wang et al, 2021;Gao et al, 2022). However, the function of m6A modification in SCI has yet to be fully elucidated.…”