Publication Date:
2016-04-29
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850741/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850741/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Titov, Denis V -- Cracan, Valentin -- Goodman, Russell P -- Peng, Jun -- Grabarek, Zenon -- Mootha, Vamsi K -- R01 GM099683/GM/NIGMS NIH HHS/ -- R01GM099683/GM/NIGMS NIH HHS/ -- T32 DK007191/DK/NIDDK NIH HHS/ -- T32DK007191/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Apr 8;352(6282):231-5. doi: 10.1126/science.aad4017. Epub 2016 Apr 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. Broad Institute, Cambridge, MA, USA. ; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA. ; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. ; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. Broad Institute, Cambridge, MA, USA. ; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. Broad Institute, Cambridge, MA, USA. vamsi@hms.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27124460" target="_blank"〉PubMed〈/a〉
Keywords:
Catalysis
;
Cytosol/enzymology
;
Electron Transport
;
Electron Transport Chain Complex Proteins/genetics/*metabolism
;
Genetic Complementation Test
;
Gluconeogenesis/*genetics
;
HeLa Cells
;
Humans
;
Lactobacillus brevis/enzymology/genetics
;
Mitochondria/*metabolism
;
Mitochondrial Diseases/enzymology/genetics
;
Multienzyme Complexes/genetics/*metabolism
;
NAD/*metabolism
;
NADH, NADPH Oxidoreductases/genetics/*metabolism
;
Oxidation-Reduction
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
