MEKK3-MEK5-ERK5 Signaling Promotes Mitochondrial Degradation

Abstract

Mitochondria are vital organelles that coordinate cellular energy homeostasis and have important roles in cell death. Therefore, the removal of damaged or excessive mitochondria is critical for maintaining proper cellular function. The PINK1-Parkin pathway removes acutely damaged mitochondria through a well-characterized mitophagy pathway, but basal mitochondrial turnover occurs via distinct and less well-understood mechanisms. Here we report that the MEKK3-MEK5-ERK5 kinase cascade is required for mitochondrial degradation in the absence of exogenous damage. We demonstrate that genetic or pharmacological inhibition of the MEKK3-MEK5-ERK5 pathway increases mitochondrial content by reducing lysosome-mediated degradation of mitochondria under basal conditions. We show that the MEKK3-MEK5-ERK5 pathway plays a selective role in basal mitochondrial degradation but is not required for non-selective bulk autophagy, damage-induced mitophagy, or restraint of mitochondrial biogenesis. This illuminates the MEKK3-MEK5-ERK5 pathway as a positive regulator of mitochondrial degradation that acts independently of exogenous mitochondrial stressors.

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“…It is noteworthy that the list of genes from the AD core modules with supporting genetic evidence (Table 1) includes a gene of the MAPK pathway, MAP3K3. This gene encodes MEKK3, a kinase acting upstream of ERK5 described as a positive regulator of mitophagy 71 . Interestingly, the dysfunction of the www.nature.com/scientificreports/ autophagy-lysosomal system and in particular the mitophagy impairment has been observed in AD patients and AD animal models 72 , and the dysregulation of the MAPK signaling pathway could be involved in this process.…”

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“…MAP3K3 is the key kinase of the MAPK signaling pathway and plays a crucial role in cell proliferation, apoptosis, and inflammatory and immune responses [58]. Previous studies showed that MAP3K3 plays a role in promoting cell survival, and MAP3K3 could promote mitochondrial degradation through the MAP3K3/MEK5/ERK5 pathway, thus increasing the content of mitochondria [59], while overexpression of Map3k3 offers resistance to apoptosis via activating the nuclear factor κB signal pathway [60]. More recently, Yuan et al determined that the Map3k2/3 deficiency led to increased total ROS from neutrophils upon stimulation by fMLP, MIP2, or PMA, indicating the importance of kinase activity in the regulation of ROS release [61].…”