TY - JOUR
T1 - Mitochondrial NDUFS3 regulates the ROS-mediated onset of metabolic switch in transformed cells
AU - Suhane, Sonal
AU - Kanzaki, Hirotaka
AU - Arumugaswami, Vaithilingaraja
AU - Murali, Ramachandran
AU - Ramanujan, V. Krishnan
N1 - Funding Information:
We gratefully acknowledge financial support from Susan G. Komen for the Cure foundation (Career Catalyst Research Award no. KG090239), National Cancer Institute/National Institutes of Health (ARRA Stimulus Award no. R21-CA124843), Donna and Jesse Garber Foundation award and American Cancer Society Inc. (Research Scholar Award RSG-12-144-01-CCE) (all to V.K.R). We thank Dr Bruce Gewertz and Dr Leon Fine for their intramural support and encouragement.
PY - 2013/3/15
Y1 - 2013/3/15
N2 - Aerobic glycolysis in transformed cells is an unique metabolic phenotype characterized by a hyperactivated glycolytic pathway even in the presence of oxygen. It is not clear if the onset of aerobic glycolysis is regulated by mitochondrial dysfunction and, if so, what the metabolic windows of opportunity available to control this metabolic switch (mitochondrial to glycolytic) landscape are in transformed cells. Here we report a genetically-defined model system based on the gene-silencing of a mitochondrial complex I subunit, NDUFS3, where we demonstrate the onset of metabolic switch in isogenic human embryonic kidney cells by differential expression of NDUFS3. By means of extensive metabolic characterization, we demonstrate that NDUFS3 gene silencing systematically introduces mitochondrial dysfunction thereby leading to the onset of aerobic glycolysis in a manner dependent on NDUFS3 protein levels. Furthermore, we show that the sustained imbalance in free radical dynamics is a necessary condition to sustain the observed metabolic switch in cell lines with the most severe NDUFS3 suppression. Together, our data reveal a novel role for mitochondrial complex I subunit NDUFS3 in regulating the degree of mitochondrial dysfunction in living cells, thereby setting a "metabolic threshold" for the observation of aerobic glycolysis phenotype within the confines of mitochondrial dysfunction.
AB - Aerobic glycolysis in transformed cells is an unique metabolic phenotype characterized by a hyperactivated glycolytic pathway even in the presence of oxygen. It is not clear if the onset of aerobic glycolysis is regulated by mitochondrial dysfunction and, if so, what the metabolic windows of opportunity available to control this metabolic switch (mitochondrial to glycolytic) landscape are in transformed cells. Here we report a genetically-defined model system based on the gene-silencing of a mitochondrial complex I subunit, NDUFS3, where we demonstrate the onset of metabolic switch in isogenic human embryonic kidney cells by differential expression of NDUFS3. By means of extensive metabolic characterization, we demonstrate that NDUFS3 gene silencing systematically introduces mitochondrial dysfunction thereby leading to the onset of aerobic glycolysis in a manner dependent on NDUFS3 protein levels. Furthermore, we show that the sustained imbalance in free radical dynamics is a necessary condition to sustain the observed metabolic switch in cell lines with the most severe NDUFS3 suppression. Together, our data reveal a novel role for mitochondrial complex I subunit NDUFS3 in regulating the degree of mitochondrial dysfunction in living cells, thereby setting a "metabolic threshold" for the observation of aerobic glycolysis phenotype within the confines of mitochondrial dysfunction.
KW - Aerobic glycolysis
KW - Metabolic switch
KW - Mitochondrial complex I
KW - Mitochondrial dysfunction
KW - NDUFS3
KW - Reactive oxygen species
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U2 - 10.1242/bio.20133244
DO - 10.1242/bio.20133244
M3 - Article
AN - SCOPUS:84965053068
VL - 2
SP - 295
EP - 305
JO - Biology Open
JF - Biology Open
SN - 2046-6390
IS - 3
ER -