Identification of Elongation Factor-2 as a Novel Regulator of
Mitochondria continuously undergo morphologically dynamic processes of
fusion and fission to maintain their size, shape, amount, and function;
yet the precise molecular mechanisms by which mitochondrial dynamics is
regulated remain to be fully elucidated. Here, we report a previous
unappreciated but critical role of eukaryotic elongation factor 2 (eEF2)
in regulating mitochondrial fission. eEF2, a G-protein superfamily
member encoded by EEF2 gene in human, has long been appreciated as a
promoter of the GTP-dependent translocation of the ribosome during
protein synthesis. We found unexpectedly in several types of cells that
eEF2 was not only present in the cytosol but also in the mitochondria.
Furthermore, we showed that mitochondrial length was significantly
increased when the cells were subjected to silencing of eEF2 expression,
suggesting a promotive role for eEF2 in the mitochondrial fission.
Inversely, overexpression of eEF2 decreased mitochondrial length,
suggesting an increase of mitochondrial fission. Inhibition of
mitochondrial fission caused by eEF2 depletion was accompanied by
alterations of cellular metabolism, as evidenced by a reduction of
oxygen consumption and an increase of oxidative stress in the
mitochondria. We further demonstrated that eEF2 and Drp1, a key driver
of mitochondrial fission, co-localized at the mitochondria, as evidenced
by microscopic observation, co-immunoprecipitation, and GST pulldown
assay. Deletion of the GTP binding motif of eEF2 decreased its
association with Drp1 and abrogated its effect on mitochondria fission.
Moreover, we showed that wild-type eEF2 stimulated GTPase activity of
Drp1, whereas deletion of the GTP binding site of eEF2 diminished its
stimulatory effect on GTPase activity. This work not only reveals a
previously unrecognized function of eEF2 (i.e., promoting mitochondrial
fission), but also uncovers the interaction of eEF2 with Drp1 as a novel
regulatory mechanism of the mitochondrial dynamics. Therefore, eEF2
warrants further exploration for its potential as a therapeutic target
for the mitochondria-related diseases.