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Mitochondrial O-GlcNAc Transferase (mOGT) Regulates Mitochondrial Structure,
Function, and Survival in HeLa Cells
#MMPMID28100784
Sacoman JL
; Dagda RY
; Burnham-Marusich AR
; Dagda RK
; Berninsone PM
J Biol Chem
2017[Mar]; 292
(11
): 4499-4518
PMID28100784
show ga
O-Linked N-acetylglucosamine transferase (OGT) catalyzes O-GlcNAcylation of
target proteins and regulates numerous biological processes. OGT is encoded by a
single gene that yields nucleocytosolic and mitochondrial isoforms. To date, the
role of the mitochondrial isoform of OGT (mOGT) remains largely unknown. Using
high throughput proteomics, we identified 84 candidate mitochondrial
glycoproteins, of which 44 are novel. Notably, two of the candidate glycoproteins
identified (cytochrome oxidase 2 (COX2) and NADH:ubiquinone oxidoreductase core
subunit 4 (MT-ND4)) are encoded by mitochondrial DNA. Using siRNA in HeLa cells,
we found that reducing endogenous mOGT expression leads to alterations in
mitochondrial structure and function, including Drp1-dependent mitochondrial
fragmentation, reduction in mitochondrial membrane potential, and a significant
loss of mitochondrial content in the absence of mitochondrial ROS. These defects
are associated with a compensatory increase in oxidative phosphorylation per
mitochondrion. mOGT is also critical for cell survival; siRNA-mediated knockdown
of endogenous mOGT protected cells against toxicity mediated by rotenone, a
complex I inhibitor. Conversely, reduced expression of both nucleocytoplasmic
(ncOGT) and mitochondrial (mOGT) OGT isoforms is associated with increased
mitochondrial respiration and elevated glycolysis, suggesting that ncOGT is a
negative regulator of cellular bioenergetics. Last, we determined that mOGT is
probably involved in the glycosylation of a restricted set of mitochondrial
targets. We identified four proteins implicated in mitochondrial biogenesis and
metabolism regulation as candidate substrates of mOGT, including leucine-rich
PPR-containing protein and mitochondrial aconitate hydratase. Our findings
suggest that mOGT is catalytically active in vivo and supports mitochondrial
structure, health, and survival, whereas ncOGT predominantly regulates cellular
bioenergetics.
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