mtDNA as a Mediator for Expression of Hypoxia-Inducible Factor 1 alpha and ROS in Hypoxic Neuroblastoma Cells

作者：Kuo Chung Wen; Tsai Meng Han; Lin Tsu Kung; Tiao Mao Meng; Wang Pei Wen; Chuang Jiin Haur; Chen Shang Der; Liou Chia Wei^*

来源：International Journal of Molecular Sciences, 2017, 18(6): 1220.

DOI：10.3390/ijms18061220

• hypoxia
• HIF-1 alpha
• DRP1
• ROS
• mtDNA

Mitochondria consume O-2 to produce ATP and are critical for adaption of hypoxia, but the role of mitochondria in HIF-1 pathway is as yet unclear. In this study, mitochondrial DNA (mtDNA) enriched (SK-N-AS) and depleted (rho(0)) cells of neuroblastoma were cultured in a hypoxic chamber to simulate a hypoxic condition and then the major components involved in mitochondrial related pathways, hypoxia-inducible factor 1 alpha (HIF-1 alpha) and reactive oxygen species (ROS) were measured. The results showed that hypoxia-stimulated exposure elevated expression of HIF-1 alpha, which was additionally influenced by level of generated ROS within the cytosol. Moreover, elevation of HIF-1 alpha also resulted in increases of lactate dehydrogenase A (LDH-A) and pyruvate dehydrogenase kinase 1 (PDK1) in both hypoxic cells. The expression of mitochondrial biogenesis related proteins and metabolic components were noted to increase significantly in hypoxic SK-N-AS cells, indicating that mtDNA was involved in mitochondrial retrograde signaling and metabolic pathways. An analysis of dynamic proteins found elevated levels of HIF-1 alpha causing an increased expression of dynamin-related protein 1 (DRP1) during hypoxia; further, the existence of mtDNA also resulted in higher expression of DRP1 during hypoxia. By using siRNA of HIF-1 alpha or DRP1, expression of DRP1 decreased after suppression of HIF-1 alpha; moreover, the expression of HIF-1 alpha was also affected by the suppression of DRP1. In this study, we demonstrated that mtDNA is a mediator of HIF-1 alpha in eliciting metabolic reprogramming, and mitochondrial biogenesis. Identification of a mutual relationship between HIF-1 alpha and DRP1 may be a critical tool in the future development of clinical applications.

• 出版日期2017-6
• 单位长春大学