IGFBP-Mediated Local and Systemic Effects of Mitochondrial Dysfunction in Skeletal Muscles

Columbia University Health Sciences, New York NY

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Abstract

PROJECT SUMMARY When mitochondrial function is impaired in a specific tissue, the tissue activates a pro-survival signaling network that includes chaperones, antioxidant enzymes, structural proteins, metabolic enzymes and non- coding RNAs. The manner of activation runs the gamut from transcriptional induction of genes, to increased stability of transcripts, to posttranslational modification of important biosynthetic proteins within the stressed tissue. However, recent evidence has shown that superimposed on these largely autonomous (local) effects, are non-autonomous (systemic) responses where the stressed tissue secretes peptides and other factors that culminate in the activation of specific signaling cascades and molecular programs in distal tissues or across the whole organism. We have found that when mitochondrial function is impaired in skeletal muscles of Drosophila, insulin signaling is downregulated locally (within the muscles) as well as systemically (across the whole organism). This is due to the upregulation of ImpL2 ? a peptide with functions analogous to insulin-like growth factor binding proteins (IGFBPs) in humans ? that systemically downregulates insulin signaling. In this proposal we will extend these previous studies to unravel the complete molecular and cellular mechanism by which ImpL2 regulates mitochondrial stress signaling across the whole organism.