Mitochondria and hypoxia-induced gene expression mediated by hypoxia-inducible factors

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.