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  • The following are the supplementary data related to this

    2021-09-23

    The following are the supplementary data related to this article.
    Transparency document
    Introduction Hypoxia is a pathological process that causes abnormal changes in metabolism, function and morphological structure of tissue because of insufficient oxygen supply. It's reported that hypoxia was accompanied with increased production of reactive oxygen species (ROS), thus provoking oxidative stress [1]. ROS is a double-edged sword: low level of ROS is a key signaling molecule in lots of pathophysiologic processes, while excessive ROS plays critical roles in damaging cellular components and initiating cell death [2]. Hypoxia inducible factor-1 (HIF-1), a crucial transcription factor in the cellular response to hypoxia, is a heterodimer composed of a constitutively expressed β subunit and an O2-regulated α subunit. Under normoxic conditions, α subunit levels are regulated by ubiquitin-dependent proteasomal degradation. Conserved proline residues in the subunit are hydroxylated by O2-dependent prolyl hydroxylases (PHDs), and the modified residues are then ubiquitinated by the p-VHL-containing E3 ubiquitin ligase complex and Dexlansoprazole degraded by the proteasome. However, under hypoxia, the HIF-1α subunit is stabilized due to inhibition of PHDs and thus accumulates in the nucleus [3]. HIF-1 binds to hypoxia-response elements and regulates the transcription of hundreds of genes involved in diverse processes such as erythropoiesis, angiogenesis, metabolic reprogramming, cell proliferation and apoptosis/survival, in response to hypoxia [4]. Mitochondria are the powerhouses of the cell and act as O2 sensors that not only generate ATP to fuel cellular processes but also represent a physical point of convergence for many oxidative stress-induced signals. Moreover, mitochondria are the main source of intracellular ROS in hypoxic Dexlansoprazole [5]. As such, mitochondria play an important role in cell fate determination under hypoxia. When O2 levels drop, there is an imbalance between O2 and electron flow in the respiratory chain, resulting in excessive production of ROS in respiratory chain complexes, increased oxidation of macromolecules, and subsequent cellular dysfunction or death. Several studies have shown that HIF-1 reduces cellular ROS production by switching energy production from oxidative phosphorylation to glycolysis via multiple pathways [6]. For instance, HIF-1 represses mitochondrial respiration and electron transfer chain activity by activating transcription of the microRNA miR-201, which reduces expression of the iron–sulfur cluster assembly proteins ISCU1/2 and NDUFA4L2, thereby decreasing complex I activity [7]. HIF-1 also activates transcription of genes encoding glucose transporters and glycolytic enzymes, which increases flux from glucose to lactate [8]. In addition, HIF-1 activates the apoptotic protein BNIP3, which induces mitochondrial-selective autophagy under hypoxia [9]. Until recently, HIF-1-dependent regulation of mitochondrial function was thought to depend directly or indirectly on HIF-1 nuclear translocation. However, several studies have reported that HIF-1α localizes to the mitochondria after hypoxic exposure or preconditioning [10], [11]. Mylonis et al. also identified HIF-1α-mortalin-VDAC1-HK-II complex at mitochondrial outer membrane which inhibits hypoxia-induced apoptosis [12]. Here, we further investigated HIF-1α protein trafficking to mitochondria in more human cancerous and normal cell lines. We found that a small fraction of HIF-1α trafficked to the mitochondria after chemical or hypoxic stabilization in a highly reproducible manner. We also confirmed this phenomena in vivo. To study the specific functions of this subpopulation of HIF-1α (here referred to as mtHIF-1α), we expressed mutant proteins (termed mito-HIF-1α) that translocated only to the mitochondria. Our findings further elucidated the new mechanism for direct regulation of mitochondria by HIF-1α independently of its transcriptional activity.