Mitochondria and Hypoxia‐induced Gene Expression Mediated by Hypoxia‐inducible Factors

Abstract

The influence of mitochondrial activity on gene expression programs, particularly those involved in neuroprotection and repair, is likely to play an important role in the pathophysiology of neurodegenerative diseases. One such gene expression program is activated by the cellular pathway that senses a decrease in optimal oxygen levels and leads to activation of a family of transcriptional activators called hypoxia-inducible factors (HIFs). HIFs are members of the bHLH-PAS family of transcription factors and are heterodimers composed of HIF-alpha and HIF-beta (also known as aryl hydrocarbon receptor nuclear translocator) subunits that bind to canonical DNA sequences (hypoxia-regulated elements) in the promoters or enhancers of target genes. HIFs activate the expression of more than a hundred genes encoding proteins that regulate cell metabolism, survival, angiogenesis, vascular tone, hematopoiesis, and other functions. There is considerable evidence showing a bidirectional crosstalk between mitochondrial signals and HIF activity. For instance, mitochondrial reactive oxygen species and metabolic substrates from the tricarboxylic acid cycle are implicated in the regulation of the HIF pathway. Conversely, HIF activity leads to the expression of target genes that influence mitochondrial function. In this chapter we will review the complex interactions between mitochondria and the HIF pathway and we will discuss the relevance of this interaction for metabolic adaptation to hypoxia.

Proteomic analysis of mitochondrial proteins in cardiomyocytes from rats subjected to intermittent hypoxia

“…Some researchers have found that IH training can affect many nuclear transcription regulators, such as hypoxiainducible transcription factors (HIFs) (Chavez et al 2008;Zhao et al 2008), Janus kinase/signal transducer and activator of transcription factor(JAK/STAT) (Volgin and Kubin 2006) and c-fos (Nanduri et al 2008), to activate cell signal transduction pathways. HIFs activate the expression of more than a 100 proteins that regulate cell metabolism, survival, angiogenesis, vascular tone, hematopoiesis and other functions (Manalo et al 2005).…”

Reactive oxygen species and vascular biology: implications in human hypertension

“…[124][125][126][127][128] ROS, through the regulation of hypoxia-inducible factor-1, are also important in O 2 sensing, 125 which is essential for maintaining normal O 2 homeostasis. In pathological conditions ROS are involved in inflammation, endothelial dysfunction, cell proliferation, migration and activation, extracellular matrix deposition, fibrosis, angiogenesis and vascular remodeling [129][130][131] ( Figure 3). …”

MitoKATP channels promote the proliferation of hypoxic human pulmonary artery smooth muscle cells via the ROS/HIF/miR‑210/ISCU signaling pathway

“…In accordance with this assumption, the present data indicated that mitoK ATP channel opening participates in the chronic proliferation of hPASMCs in collaboration with HIF-1α under hypoxic conditions. miR-210, which is upregulated by HIF-1α, is considered to be among the most hypoxia-sensitive miRs and a microregulator of the hypoxia pathway (34). As a downstream target of miR-210 (12,33,35), ISCU is responsible for the assembly of iron sulfur clusters [Fe-S] in mitochondrial respiratory complexes (complexes I, II and III) (21,36).…”