Mortalin-mediated and ERK-controlled targeting of HIF-1α to mitochondria confers resistance to apoptosis under hypoxia

Abstract

Hypoxia inducible factor-1 (HIF-1) is the main transcriptional activator of the cellular response to hypoxia and an important target of anticancer therapy. Phosphorylation by ERK1 and/or ERK2 (MAPK3 and MAPK1, respectively; hereafter ERK) stimulates the transcriptional activity of HIF-1α by inhibiting its CRM1 (XPO1)-dependent nuclear export. Here, we demonstrate that phosphorylation by ERK also regulates the association of HIF-1α with a so-far-unknown interaction partner identified as mortalin (also known as GRP75 and HSPA9), which mediates non-genomic involvement of HIF-1α in apoptosis. Mortalin binds specifically to HIF-1α that lacks modification by ERK, and the HIF-1α-mortalin complex is localized outside the nucleus. Under hypoxia, mortalin mediates targeting of unmodified HIF-1α to the outer mitochondrial membrane, as well as association with VDAC1 and hexokinase II, which promotes production of a C-terminally truncated active form of VDAC1, denoted VDAC1-ΔC, and protection from apoptosis when ERK is inactivated. Under normoxia, transcriptionally inactive forms of unmodified HIF-1α or its C-terminal domain alone are also targeted to mitochondria, stimulate production of VDAC1-ΔC and increase resistance to etoposide-or doxorubicin-induced apoptosis. These findings reveal an ERK-controlled, unconventional and anti-apoptotic function of HIF-1α that might serve as an early protective mechanism upon oxygen limitation and promote cancer cell resistance to chemotherapy.

The regulation of mitochondrial dynamics in neurite outgrowth by retinoic acid receptor β signaling

“…The mitochondrion-associated stress chaperone GRP75 has recently been described to play a role in neuronal ER–mitochondrial coupling and sensitivity to oxidative stress and hypoxia, in a process involving HIF-1α (10, 25). Because GR75 is highly linked with mitochondrial response to hypoxia and oxygen limitation (11, 12), and considering that it has been shown to bind RARs (26), we next looked at its expression levels to further clarify its role in mediating the process of mitochondrial recruitment to the growing neurite.…”

“…Besides regulating mitochondrial activity, HIF-1a induces the expression of the modulator of mitochondrial movement, hypoxia up-regulated mitochondrial movement regulator (HUMMR), which promotes mitochondrial movement toward the distal part of neurites and synapses (7) by interacting with the transport enzymes mitochondrial Rho GTPase (MIRO) 1 and 2 (8,9). Additionally, the mitochondrial stress chaperone glucoserelated protein 75 (GRP75), a mediator of endoplasmic reticulum (ER)-mitochondrial coupling, has recently been associated with HIF-1a-mediated mitochondrial response to hypoxia (10)(11)(12).…”

ERK1/2 phosphorylates HIF-2α and regulates its activity by controlling its CRM1-dependent nuclear shuttling

“…and translocation to the cytoplasm, HIF-1α interacts with proteins of the outer mitochondrial membrane forming an anti-apoptotic complex (Mylonis et al, 2017). This leaves open the possibility that the regulation of the nucleocytoplasmic distribution of HIF-2α by ERK1/ 2 may not only serve the control of HIF-2-target gene expression but also a cytoplasmic function of HIF-2α such as the one involving the Fig.…”

Cinobufagin suppresses colorectal cancer angiogenesis by disrupting the endothelial mammalian target of rapamycin/hypoxia‐inducible factor 1α axis

“…HIF‐1 suppresses mitochondrial function and promotes the efficient use of available oxygen. Therefore, HIF‐1α reduces the generation of ROS and confers apoptosis resistance to cancer cells . Evasion of apoptosis may represent an important hallmark of many human cancers.…”

“…39 resistance to cancer cells. 40 Evasion of apoptosis may represent an important hallmark of many human cancers. Cinobufagin reduces neovascularization by increasing the ROS level which leads to mitochondrial dysfunction in endothelial cells.…”