Reports suggest that silent information regulation 2 homolog 3 (
SIRT3) protects cardiomyocytes from oxidative stress-mediated death.
SIRT3, a
mitochondrial protein, is an essential regulator of mitochondrial function, and this regulation is important in many
cerebrovascular diseases, especially
stroke. Here, we investigated the role of
SIRT3 in
ischemia-induced neuronal death due to
oxygen-
glucose deprivation (OGD) using an in vitro model of
cerebral ischemia. We found that exposure of differentiated PC12 cells to OGD for 6h caused a marked decrease in cell viability and up regulated
SIRT3.
SIRT3 knockdown using
short interfering RNA (
siRNA) exacerbated OGD-induced injury whereas application of recombinant
SIRT3 protected against OGD-induced cell death. Pre-treatment of the cells in which the
SIRT3 gene was knocked down with recombinant
SIRT3 before OGD partially restored cell viability and concomitantly reduced
lactate dehydrogenase (LDH) release and increased
ATP generation in mitochondria. Recombinant
SIRT3 treatment resulted in increased expression of
peroxisome proliferator activated receptor (
PPAR)-γ co-activator 1-α (PGC-1α) and
manganese superoxide dismutase (MnSOD). After knockdown of PGC-1α or MnSOD, recombinant
SIRT3 failed to protect against OGD-induced injury. We also found that the
protein and
mRNA expression of PGC-1α was down regulated following
SIRT3 knockdown. The expression level of
SIRT3 was reduced when the PGC-1α gene was knocked down. Both
SIRT3 and PGC-1α knockdown led to reduced mitochondrial membrane potential (Δψ) and Ca(2+) transients, especially under OGD conditions. Thus, our data suggest that
SIRT3 protects PC12 cells from hypoxic injury via a mechanism that may involve PGC-1α and MnSOD.
SIRT3 and PGC-1α regulate each other under physiologic and OGD conditions, thereby partially protecting against
hypoxia or
ischemia.