Complementation of mitochondrial electron transport chain by manipulation of the NAD+/NADH ratio.

Science
Authors
Keywords
Abstract

A decline in electron transport chain (ETC) activity is associated with many human diseases. Although diminished mitochondrial adenosine triphosphate production is recognized as a source of pathology, the contribution of the associated reduction in the ratio of the amount of oxidized nicotinamide adenine dinucleotide (NAD(+)) to that of its reduced form (NADH) is less clear. We used a water-forming NADH oxidase from Lactobacillus brevis (LbNOX) as a genetic tool for inducing a compartment-specific increase of the NAD(+)/NADH ratio in human cells. We used LbNOX to demonstrate the dependence of key metabolic fluxes, gluconeogenesis, and signaling on the cytosolic or mitochondrial NAD(+)/NADH ratios. Expression of LbNOX in the cytosol or mitochondria ameliorated proliferative and metabolic defects caused by an impaired ETC. The results underscore the role of reductive stress in mitochondrial pathogenesis and demonstrate the utility of targeted LbNOX for direct, compartment-specific manipulation of redox state.

Year of Publication
2016
Journal
Science
Volume
352
Issue
6282
Pages
231-5
Date Published
2016 Apr 08
ISSN
1095-9203
URL
DOI
10.1126/science.aad4017
PubMed ID
27124460
PubMed Central ID
PMC4850741
Links
Grant list
R01 GM099683 / GM / NIGMS NIH HHS / United States
T32 DK007191 / DK / NIDDK NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
T32DK007191 / DK / NIDDK NIH HHS / United States
Howard Hughes Medical Institute / United States
R01GM099683 / GM / NIGMS NIH HHS / United States