TY - JOUR
T1 - A Mitochondrial RNAi Screen Defines Cellular Bioenergetic Determinants and Identifies an Adenylate Kinase as a Key Regulator of ATP Levels
AU - Lanning, Nathan J.
AU - Looyenga, Brendan D.
AU - Kauffman, Audra L.
AU - Niemi, Natalie M.
AU - Sudderth, Jessica
AU - DeBerardinis, Ralph J.
AU - MacKeigan, Jeffrey P.
N1 - Funding Information:
We thank members of the J.P.M. laboratory for their insights and critical feedback. This work was supported by NIH National Cancer Institute grants R01CA138651 (to J.P.M.), R01CA157996 (to R.J.D.), and F32CA159709 (to N.J.L.). This work utilized Core Services supported by grant DK097153 from the NIH to the University of Michigan.
PY - 2014
Y1 - 2014
N2 - Altered cellular bioenergetics and mitochondrial function are major features of several diseases, including cancer, diabetes, and neurodegenerative disorders. Given this important link to human health, we sought to define proteins within mitochondria that are critical for maintaining homeostatic ATP levels. We screened an RNAi library targeting >1,000 nuclear-encoded genes whose protein products localize to the mitochondria in multiple metabolic conditions in order to examine their effects on cellular ATP levels. We identified a mechanism by which electron transport chain (ETC) perturbation under glycolytic conditions increased ATP production through enhanced glycolytic flux, thereby highlighting the cellular potential for metabolic plasticity. Additionally, we identified a mitochondrial adenylate kinase (AK4) that regulates cellular ATP levels and AMPK signaling and whose expression significantly correlates with glioma patient survival. This study maps the bioenergetic landscape of >1,000 mitochondrial proteins in the context of varied metabolic substrates and begins to link key metabolic genes with clinical outcome.
AB - Altered cellular bioenergetics and mitochondrial function are major features of several diseases, including cancer, diabetes, and neurodegenerative disorders. Given this important link to human health, we sought to define proteins within mitochondria that are critical for maintaining homeostatic ATP levels. We screened an RNAi library targeting >1,000 nuclear-encoded genes whose protein products localize to the mitochondria in multiple metabolic conditions in order to examine their effects on cellular ATP levels. We identified a mechanism by which electron transport chain (ETC) perturbation under glycolytic conditions increased ATP production through enhanced glycolytic flux, thereby highlighting the cellular potential for metabolic plasticity. Additionally, we identified a mitochondrial adenylate kinase (AK4) that regulates cellular ATP levels and AMPK signaling and whose expression significantly correlates with glioma patient survival. This study maps the bioenergetic landscape of >1,000 mitochondrial proteins in the context of varied metabolic substrates and begins to link key metabolic genes with clinical outcome.
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U2 - 10.1016/j.celrep.2014.03.065
DO - 10.1016/j.celrep.2014.03.065
M3 - Article
C2 - 24767988
AN - SCOPUS:84899828061
SN - 2211-1247
VL - 7
SP - 907
EP - 917
JO - Cell Reports
JF - Cell Reports
IS - 3
ER -