Analysis Tools
mortality/aging
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• no viable mice are produced; homozygoys embryos fail to develop beyond ~E12.5
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cellular
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• mouse embryonic fibroblasts (MEFs) derived from ~E11.5 embryos show a vastly increased number of autophagosomes relative to wild-type MEFs
• LC3 mRNA levels and cellular levels of the active lipidated protein form (LC3-II) are significantly higher than those in wild-type MEFs
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• MEFs show a significant increase in the transcript and protein levels of TFEB (transcription factor EB, a master regulator of autophagic and lysosomal pathways) and its downstream targets (LAMP1 and p62), indicating an increased TFEB-mediated mitophagy rate
• however, TFEB, p62, LAMP1, and LC3-II proteins are localized in the correct cellular compartment
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• MEFs are deficient in their maximal uncoupled respiration rate, reserve capacity and use of oxygen for ATP synthesis
• mitochondrial energetic defects are counterbalanced by increased glycolysis, both at baseline and following stimulation with glucose
• MEFs show a significant induction in the expression of several mitochondrial biogenesis genes, especially Ppargc1a (PGC-1alpha), to counteract the increased TFEB-mediated mitophagy rate, resulting in an increased mitochondrial turnover rate
• however, mitochondrial protein levels, mtDNA copy number and mitochondrial volume remain normal
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homeostasis/metabolism
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• mouse embryonic fibroblasts (MEFs) derived from ~E11.5 embryos show a vastly increased number of autophagosomes relative to wild-type MEFs
• LC3 mRNA levels and cellular levels of the active lipidated protein form (LC3-II) are significantly higher than those in wild-type MEFs
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• MEFs show a significant increase in the transcript and protein levels of TFEB (transcription factor EB, a master regulator of autophagic and lysosomal pathways) and its downstream targets (LAMP1 and p62), indicating an increased TFEB-mediated mitophagy rate
• however, TFEB, p62, LAMP1, and LC3-II proteins are localized in the correct cellular compartment
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