RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis

Abstract

Aerobic glycolysis or the Warburg effect contributes to cancer cell proliferation; however, how this glucose metabolism pathway is precisely regulated remains elusive. Here we show that receptor-interacting protein 1 (RIP1), a cell death and survival signaling factor, regulates mitochondrial oxidative phosphorylation and aerobic glycolysis. Loss of RIP1 in lung cancer cells suppressed peroxisome proliferator-activated receptor c coactivator-1a (PGC-1a) expression, impairing mitochondrial oxidative phosphorylation and accelerating glycolysis, resulting in spontaneous DNA damage and p53-mediated cell proliferation inhibition. Thus, although aerobic glycolysis within a certain range favors cancer cell proliferation, excessive glycolysis causes cytostasis. Our data suggest that maintenance of glycolysis by RIP1 is pivotal to cancer cell energy homeostasis and DNA integrity and may be exploited for use in anticancer therapy. A cell's metabolism is optimized for its function and adapts to environmental changes; therefore, it is pivotal to differentiation, proliferation, survival and death. In the presence of ample oxygen, cancer cells prefer glycolysis over mitochondrial respiration for energy supply, which is known as the Warburg effect or aerobic glycolysis.1,2 Although aerobic glycolysis was originally thought to complement impaired mitochondrial respiration, recent investigations suggest that it is a driving force in cancer cell transformation and proliferation. 3,4 In coordination with the tricarboxylic acid cycle and mitochondrial respiration, cancer cells increase glycolysis to support their rapid proliferation. This 'metabolic transformation' in cancer cells not only meets their energy requirements but also provides the building blocks for synthesis of biomass and for maintenance of redox homeostasis. 5,6 Thus, the metabolic transformation is believed to offer cancer cells a selective growth advantage compared with their normal counterparts and to contribute to drug resistance. Many oncogenes such as c-Myc and Akt, and tumor suppressors such as p53 are involved in the regulation of glycolysis and mitochondrial metabolism, serving as evidence of the necessity for metabolic adaptation in cancer cells. 7,8 However, how metabolic transformation is precisely regulated needs further elucidation.Receptor-interacting protein 1 (RIP1) is a serine/threonine kinase with functions in cell proliferation, survival and death.9-11 The role of RIP1 in cell survival is achieved mainly through its function as an adaptor in signal pathways, such as NF-kB and PI3K/Akt, that suppress apoptosis. The kinase activity of RIP1 is involved in programmed necrosis or necroptosis.12 Although RIP1 can translocate to the mitochondria in certain circumstances and can modulate ADP/ ATP exchange and the production of mitochondrial reactive oxygen species (ROS), [13][14][15][16] whether RIP1 regulates cell energy homeostasis is unknown.In an attempt to investigate the role of RIP1 in cell proliferation, we uncovered a function for this protein in...

The Role of PGC1α in Cancer Metabolism and its Therapeutic Implications

“…Loss of RIP1 suppresses PGC1a expression and OxPhos, resulting in accelerated glycolysis. However, excessive glycolysis decreases cellular NAD þ levels and impairs DNA repair, which activates p53-mediated cell growth inhibition (98,99). These data provide additional evidence supporting a reciprocal regulation between metabolic adaptation and wildtype p53 in cancer cell fate determination.…”

“…As well as the direct regulatory mechanism between PGC1a and p53, the receptor-interacting protein 1 (RIP1)/PGC1a signaling axis indirectly affects the control of p53-dependent cell proliferation (98). This signaling pathway maintains metabolic homeostasis in lung cancer cells.…”

RIP1 Kinase Is an Oncogenic Driver in Melanoma

“…NF-kB is not involved in RIP1-mediated promotion of cell proliferation in some types of cells (5,39). However, we found that NF-kB activation was critical for RIP1 to promote melanoma cell proliferation.…”

Leptin-induced mitochondrial fusion mediates hepatic lipid accumulation

“…11 Suppression of PGC-1α by receptor-interacting protein 1 knockdown impairs mitochondrial oxidative phosphorylation and acceleration of glycolysis in cancer cell. 12 Given that mitochondrial morphology affects energy imbalance and is continuously changed through fusion and fission events, a tight coordination between mitochondrial dynamics and interorganelle interactions is crucial. The fusion protein mitofusin (Mfn) 2 has been extensively implicated in mitochondrial fusion.…”