TY - JOUR
T1 - Comparative metabolomic profiling reveals that dysregulated glycolysis stemming from lack of salvage NAD+ biosynthesis impairs reproductive development in Caenorhabditis elegans
AU - Wang, Wenqing
AU - McReynolds, Melanie R.
AU - Goncalves, Jimmy F.
AU - Shu, Muya
AU - Dhondt, Ineke
AU - Braeckman, Bart P.
AU - Lange, Stephanie E.
AU - Kho, Kelvin
AU - Detwiler, Ariana C.
AU - Pacella, Marisa J.
AU - Hanna-Rose, Wendy
N1 - Publisher Copyright:
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.
PY - 2015/10/23
Y1 - 2015/10/23
N2 - Temporal developmental progression is highly coordinated in Caenorhabditis elegans. However, loss of nicotinamidase PNC-1 activity slows reproductive development, uncoupling it from its typical progression relative to the soma. Using LC/MS we demonstrate that pnc-1 mutants do not salvage the nicotinamide released by NAD+ consumers to resynthesize NAD+, resulting in a reduction in global NAD+ bioavailability. We manipulate NAD+ levels to demonstrate that a minor deficit in NAD+ availability is incompatible with a normal pace of gonad development. The NAD+ deficit compromises NAD+ consumer activity, but we surprisingly found no functional link between consumer activity and reproductive development. As a result we turned to a comparative metabolomics approach to identify the cause of the developmental phenotype. We reveal widespread metabolic perturbations, and using complementarypharmacologicalandgenetic approaches, wedemonstrate that a glycolytic block accounts for the slow pace of reproductive development. Interestingly, mitochondria are protected from both the deficiency in NAD+ biosynthesis and the effects of reduced glycolytic output. We suggest that compensatory metabolic processes that maintain mitochondrial activity in the absence of efficient glycolysis are incompatible with the requirements for reproductive development, which requires high levels of cell division. In addition to demonstrating metabolic requirements for reproductive development, this work also has implications for understanding the mechanisms behind therapeutic interventions that target NAD+ salvage biosynthesis for the purposes of inhibiting tumor growth.
AB - Temporal developmental progression is highly coordinated in Caenorhabditis elegans. However, loss of nicotinamidase PNC-1 activity slows reproductive development, uncoupling it from its typical progression relative to the soma. Using LC/MS we demonstrate that pnc-1 mutants do not salvage the nicotinamide released by NAD+ consumers to resynthesize NAD+, resulting in a reduction in global NAD+ bioavailability. We manipulate NAD+ levels to demonstrate that a minor deficit in NAD+ availability is incompatible with a normal pace of gonad development. The NAD+ deficit compromises NAD+ consumer activity, but we surprisingly found no functional link between consumer activity and reproductive development. As a result we turned to a comparative metabolomics approach to identify the cause of the developmental phenotype. We reveal widespread metabolic perturbations, and using complementarypharmacologicalandgenetic approaches, wedemonstrate that a glycolytic block accounts for the slow pace of reproductive development. Interestingly, mitochondria are protected from both the deficiency in NAD+ biosynthesis and the effects of reduced glycolytic output. We suggest that compensatory metabolic processes that maintain mitochondrial activity in the absence of efficient glycolysis are incompatible with the requirements for reproductive development, which requires high levels of cell division. In addition to demonstrating metabolic requirements for reproductive development, this work also has implications for understanding the mechanisms behind therapeutic interventions that target NAD+ salvage biosynthesis for the purposes of inhibiting tumor growth.
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U2 - 10.1074/jbc.M115.662916
DO - 10.1074/jbc.M115.662916
M3 - Article
C2 - 26350462
AN - SCOPUS:84944937157
SN - 0021-9258
VL - 290
SP - 26163
EP - 26179
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 43
ER -