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2015 ; 290
(46
): 27644-59
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Subcellular Distribution of NAD+ between Cytosol and Mitochondria Determines the
Metabolic Profile of Human Cells
#MMPMID26432643
VanLinden MR
; Dölle C
; Pettersen IK
; Kulikova VA
; Niere M
; Agrimi G
; Dyrstad SE
; Palmieri F
; Nikiforov AA
; Tronstad KJ
; Ziegler M
J Biol Chem
2015[Nov]; 290
(46
): 27644-59
PMID26432643
show ga
The mitochondrial NAD pool is particularly important for the maintenance of vital
cellular functions. Although at least in some fungi and plants, mitochondrial NAD
is imported from the cytosol by carrier proteins, in mammals, the mechanism of
how this organellar pool is generated has remained obscure. A transporter
mediating NAD import into mammalian mitochondria has not been identified. In
contrast, human recombinant NMNAT3 localizes to the mitochondrial matrix and is
able to catalyze NAD(+) biosynthesis in vitro. However, whether the endogenous
NMNAT3 protein is functionally effective at generating NAD(+) in mitochondria of
intact human cells still remains to be demonstrated. To modulate mitochondrial
NAD(+) content, we have expressed plant and yeast mitochondrial NAD(+) carriers
in human cells and observed a profound increase in mitochondrial NAD(+). None of
the closest human homologs of these carriers had any detectable effect on
mitochondrial NAD(+) content. Surprisingly, constitutive redistribution of NAD(+)
from the cytosol to the mitochondria by stable expression of the Arabidopsis
thaliana mitochondrial NAD(+) transporter NDT2 in HEK293 cells resulted in
dramatic growth retardation and a metabolic shift from oxidative phosphorylation
to glycolysis, despite the elevated mitochondrial NAD(+) levels. These results
suggest that a mitochondrial NAD(+) transporter, similar to the known one from A.
thaliana, is likely absent and could even be harmful in human cells. We provide
further support for the alternative possibility, namely intramitochondrial NAD(+)
synthesis, by demonstrating the presence of endogenous NMNAT3 in the mitochondria
of human cells.
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