Polyunsaturated Fatty Acid Desaturation Is a Mechanism for Glycolytic NAD+ Recycling

Wondong Kim; Amy Deik; Clicerio Gonzalez; Maria Elena Gonzalez; Feifei Fu; Michele Ferrari; Claire L Churchhouse; Jose C Florez; Suzanne B R Jacobs; Clary B Clish; Eugene P Rhee

doi:10.1016/j.cmet.2018.12.023

Polyunsaturated Fatty Acid Desaturation Is a Mechanism for Glycolytic NAD⁺ Recycling

Cell Metab. 2019 Apr 2;29(4):856-870.e7. doi: 10.1016/j.cmet.2018.12.023. Epub 2019 Jan 24.

Authors

Affiliations

¹ Nephrology Division, Massachusetts General Hospital, Boston, MA 02114, USA; Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
² Metabolite Profiling, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ Unidad de Investigación en Diabetes y Riesgo Cardiovascular, Instituto Nacional de Salud Publica, Curenavaca, Mexico.
⁴ Centro de Estudios en Diabetes A.C., Mexico City, Mexico.
⁵ Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁷ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁸ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Metabolism Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Metabolite Profiling, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Metabolism Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: clary@broadinstitute.org.
¹⁰ Nephrology Division, Massachusetts General Hospital, Boston, MA 02114, USA; Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Metabolism Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: eprhee@partners.org.

Abstract

The reactions catalyzed by the delta-5 and delta-6 desaturases (D5D/D6D), key enzymes responsible for highly unsaturated fatty acid (HUFA) synthesis, regenerate NAD⁺ from NADH. Here, we show that D5D/D6D provide a mechanism for glycolytic NAD⁺ recycling that permits ongoing glycolysis and cell viability when the cytosolic NAD⁺/NADH ratio is reduced, analogous to lactate fermentation. Although lesser in magnitude than lactate production, this desaturase-mediated NAD⁺ recycling is acutely adaptive when aerobic respiration is impaired in vivo. Notably, inhibition of either HUFA synthesis or lactate fermentation increases the other, underscoring their interdependence. Consistent with this, a type 2 diabetes risk haplotype in SLC16A11 that reduces pyruvate transport (thus limiting lactate production) increases D5D/D6D activity in vitro and in humans, demonstrating a chronic effect of desaturase-mediated NAD⁺ recycling. These findings highlight key biologic roles for D5D/D6D activity independent of their HUFA end products and expand the current paradigm of glycolytic NAD⁺ regeneration.

Keywords: FADS1-3; NAD(+) recycling; SLC16A11; delta-5-desaturase; delta-6-desaturase; highly unsaturated fatty acids; polyunsaturated fatty acids.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Delta-5 Fatty Acid Desaturase
Fatty Acids, Unsaturated / metabolism*
Female
Glycolysis*
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Middle Aged
NAD / metabolism*

Substances

Delta-5 Fatty Acid Desaturase
Fatty Acids, Unsaturated
NAD
FADS1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding