Abstract
Mitochondria are dynamic organelles that undergo fusion and fission in response to various physiological and stress stimuli, which play key roles in diverse mitochondrial functions such as energy metabolism, intracellular signaling, and apoptosis. OPA1, a mitochondrial dynamin-like GTPase, is responsible for the inner membrane fusion of mitochondria, and the function of OPA1 is regulated by proteolytic cleavage in response to various metabolic stresses. Growing evidences highlighted the importance of mitochondrial adaptation in response to metabolic stimuli. Here, we demonstrated the role of p32/C1QBP in mitochondrial morphology by regulating OMA1-dependent proteolytic processing of OPA1. Genetic ablation of p32/C1QBP activates OMA1, cleaves OPA1, and leads mitochondrial fragmentation and swelling. The loss of p32/C1QBP decreased mitochondrial respiration and lipid utilization, sensitized cells to mitochondrial stress, and triggered a metabolic shift from oxidative phosphorylation to glycolysis, which were correlated with apoptosis in cancer cells and the inhibition of 3D-spheroid formation. These results suggest a unique regulation of cell physiology by mitochondria and provide a basis for a new therapeutic strategy for cancer.
Highlights
Mitochondrial morphology varies widely among many cell types and tissues, changing rapidly in response to metabolic alterations, such as nutrient status[1,2,3]
Hexokinase 2 (HK2) protein level increased in p 32−/− mouse embryonic fibroblasts (MEFs) and reversed by restoring p32 expression (Fig. 7c). These results suggest that genetic deletion of p32 abolishes mitochondrial energy production and increased HK2 expression resulting in a glycolytic metabolic shift
The mitochondrion is a central organelle for cellular metabolism, including OXPHOS, the tricarboxylic acid cycle (TCA cycle), β-oxidation of fatty acids, calcium signaling, and heme b iosynthesis[36]
Summary
Mitochondrial morphology varies widely among many cell types and tissues, changing rapidly in response to metabolic alterations, such as nutrient status[1,2,3]. Mitochondria do not operate as a single separated organelle Rather, they function as a group whose activity is coordinated by mitochondrial dynamics[4]. A continuous cycle of mitochondrial membrane fusion and fission serves to mix the contents of the mitochondrial population, promote homogeneity of organelles, control the morphology of mitochondria, and maintain high functionality[4]. An unobstructed mitochondrial fusion leads to a hyperfused mitochondrial network to counteract metabolic insults, preserve cellular integrity, and protect against mitophagy and a poptosis[1, 5]. OPA1 maintains a negative cristae junction curvature in the mitochondrial inner membrane, which controls cytochrome C redistribution and release[22, 23], and stabilizes the respiratory super-complexes to increase respiratory e fficiency[24, 25]. OMA1 and YME1L coordinately regulate mitochondrial fusion and cristae structure by differential proteolytic processing of OPA130
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