Autophagy in Zellweger Syndrome Spectrum Disorder and Cancer




Lee, Ming Yeh

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Autophagy is a lysosomal degradation pathway that breaks down unwanted proteins and organelles from the cytoplasm to regenerate cellular building blocks. This process is constitutively active at low basal levels, and can be upregulated by stress stimuli to promote cellular homeostasis. In this work, we investigated two aspects of autophagy regulation and relevance to human diseases. First, we examined how autophagy selectively removes viral components and damaged mitochondria from the cytoplasm through PEX13, a peroxin protein mutated in Zellweger syndrome spectrum (ZSS). Second, we examined the role of autophagy as a potential mechanism contributing to exercise-mediated protection against cancer progression. PEX13 is an integral membrane protein on the peroxisome that regulates peroxisomal matrix protein import during peroxisome biogenesis. Mutations in PEX13 and other peroxin proteins are associated with ZSS disorders, a subtype of peroxisome biogenesis disorder characterized by prominent neurodevelopmental, hepatic, and renal abnormalities leading to neonatal death. The lack of functional peroxisomes in ZSS patients is widely accepted as the underlying cause of disease; however, our understanding of disease pathogenesis is still incomplete. Here, we demonstrate that PEX13 is required for selective autophagy of Sindbis virus (virophagy) and of damaged mitochondria (mitophagy), and that disease-associated PEX13 mutants I326T and W313G are defective in mitophagy. The selective mitophagy function of PEX13 is shared with another peroxin family member PEX3, but not with two other peroxins, PEX14 and PEX19, which are required for general autophagy. Together, our results demonstrate that PEX13 is required for selective autophagy, and suggest that dysregulation of PEX13-mediated mitophagy may contribute to ZSS pathogenesis. In the second part of this study, we evaluated physiological functions regulated by exercise-induced autophagy, including changes to the metabolome, proteome, and breast cancer progression. A previous study from our laboratory demonstrated that exercise is a potent inducer of autophagy and that autophagy contributes to exercise-mediated metabolic benefits. Therefore, we speculate that autophagy may contribute to exercise-mediated protection against other diseases. Although many epidemiological and laboratory studies have provided strong evidence that physical exercise can decrease cancer development and mortality, the mechanisms are poorly understood. Using the E0771 injectable murine breast cancer, we show that exercise delays cancer progression in wild-type, but not in Bcl-2 AAA mice or Beclin 1 heterozygous knockout mice that are deficient in exercise-induced autophagy. We identified candidate factors and pathways regulated by exercise-induced autophagy, including plasma levels of pyrimidine, branched chain amino acids, LIF, and IL-15, as well as skeletal muscle expression of IDH2 and NDUFA13. Further studies are required to elucidate the metabolomic and proteomic alterations regulated by exercise-induced autophagy and the mechanism by which exercise-induced autophagy protects against tumor progression.

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