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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.
Highlights
Maintaining a population of healthy mitochondria is vital for proper development and is necessary to preserve tissue and organ function in response to stress conditions[1]
We treated U2OS osteosarcoma cells with Bafilomycin A1 for 2 h to inhibit degradation of all cargo delivered to the lysosome and used immunofluorescent microscopy to determine whether such cargo included mitochondria and p62
Our experiments revealed that a minority of the mitochondrial population were delivered to LAMP1-positive lysosomes in the absence of any mitophagy-inducing treatment, and all LAMP1-encapsulated mitochondria were co-labeled with p62 (Fig. 1a, b)
Summary
Maintaining a population of healthy mitochondria is vital for proper development and is necessary to preserve tissue and organ function in response to stress conditions[1]. Mitochondria are well known for their importance in metabolism and energy production, but they are a major source of reactive oxygen species (ROS), cytosolic DNA, and pro-apoptotic proteins[2,3,4,5]. Damaged or dysfunctional mitochondria tend to generate higher levels of ROS and cytosolic DNA compared to healthy mitochondria[2,3,6]. To maintain homeostasis, the cell has evolved complex systems for the quality control of mitochondria[10]. These systems are designed to balance the elimination of dysfunctional or superfluous mitochondria with mitochondrial biogenesis[1]
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