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.

Public Health Relevance

These studies will lead to fundamental new insights into the mechanisms by which IGFBPs secreted from muscles relay the physiological state of muscles to other organs. In addition, it has the potential to identify novel IGFBP-dependent secreted molecules that may open up therapeutic opportunities for many chronic metabolic diseases associated with muscle mitochondrial dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK112074-02
Application #
9353787
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Waddy, Salina P
Project Start
2016-09-16
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Garcia, Christian Joel; Khajeh, Jahan; Coulanges, Emmanuel et al. (2017) Regulation of Mitochondrial Complex I Biogenesis in Drosophila Flight Muscles. Cell Rep 20:264-278