GLTSCR2/PICT1 links mitochondrial stress and Myc signaling

Mitochondrial defects underlie a multitude of human diseases. Genetic manipulation of mitochondrial regulatory pathways represents a potential therapeutic approach. We have carried out a high-throughput overexpression screen for genes that affect mitochondrial abundance or activity using flow-cytome...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 111; no. 10; pp. 3781 - 3786
Main Authors Yoon, John C., Ling, Alvin J. Y., Isik, Meltem, Lee, Dong-Young Donna, Steinbaugh, Michael J., Sack, Laura M., Boduch, Abigail N., Blackwell, T. Keith, Sinclair, David A., Elledge, Stephen J.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 11.03.2014
National Acad Sciences
Subjects
Adenosine Triphosphate - metabolism
Animals
Biological Sciences
Blotting, Western
Caenorhabditis elegans
Cell growth
Cell lines
Cells
Cells, Cultured
Databases, Genetic
DNA Primers - genetics
Flow Cytometry
Gene expression
Gene expression regulation
Genes
Genetic screening
Humans
Immunoprecipitation
Microarray Analysis
Mitochondria
Mitochondria - metabolism
Mitochondria - physiology
Open reading frames
Open Reading Frames - genetics
Oxygen consumption
Oxygen Consumption - physiology
Proto-Oncogene Proteins c-myc - metabolism
Respiration
RNA Interference
Signal transduction
Signal Transduction - physiology
Small interfering RNA
Stress, Physiological - physiology
Tumor Suppressor Proteins - metabolism
Worms
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Summary:Mitochondrial defects underlie a multitude of human diseases. Genetic manipulation of mitochondrial regulatory pathways represents a potential therapeutic approach. We have carried out a high-throughput overexpression screen for genes that affect mitochondrial abundance or activity using flow-cytometry-based enrichment of a cell population expressing a high-complexity, concentration-normalized pool of human ORFs. The screen identified 94 candidate mitochondrial regulators including the nuclear protein GLTSCR2, also known as PICT1. GLTSCR2 enhances mitochondrial function and is required for the maintenance of oxygen consumption, consistent with a pivotal role in the control of cellular respiration. RNAi inactivation of the Caenorhabditis elegans ortholog of GLTSCR2 reduces respiration in worms, indicating functional conservation across species. GLTSCR2 controls cellular proliferation and metabolism via the transcription factor Myc, and is induced by mitochondrial stress, suggesting it may constitute a significant component of the mitochondrial signaling pathway.
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1J.C.Y. and A.J.Y.L. contributed equally to this work.
Author contributions: J.C.Y., A.J.Y.L., M.I., L.M.S., T.K.B., D.A.S., and S.J.E. designed research; J.C.Y., A.J.Y.L., M.I., D.-Y.D.L., M.J.S., L.M.S., and A.N.B. performed research; J.C.Y., A.J.Y.L., T.K.B., D.A.S., and S.J.E. analyzed data; and J.C.Y., A.J.Y.L., T.K.B., D.A.S., and S.J.E. wrote the paper.
Contributed by Stephen J. Elledge, January 16, 2014 (sent for review December 28, 2013)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1400705111