[show abstract][hide abstract] ABSTRACT: Increased expression of the regulatory subunit of HIFs (HIF-1α or HIF-2α) is associated with metabolic adaptation, angiogenesis, and tumor progression. Understanding how HIFs are regulated is of intense interest. Intriguingly, the molecular mechanisms that link mitochondrial function with the HIF-regulated response to hypoxia remain to be unraveled. Here we describe what we believe to be novel functions of the human gene CHCHD4 in this context. We found that CHCHD4 encodes 2 alternatively spliced, differentially expressed isoforms (CHCHD4.1 and CHCHD4.2). CHCHD4.1 is identical to MIA40, the homolog of yeast Mia40, a key component of the mitochondrial disulfide relay system that regulates electron transfer to cytochrome c. Further analysis revealed that CHCHD4 proteins contain an evolutionarily conserved coiled-coil-helix-coiled-coil-helix (CHCH) domain important for mitochondrial localization. Modulation of CHCHD4 protein expression in tumor cells regulated cellular oxygen consumption rate and metabolism. Targeting CHCHD4 expression blocked HIF-1α induction and function in hypoxia and resulted in inhibition of tumor growth and angiogenesis in vivo. Overexpression of CHCHD4 proteins in tumor cells enhanced HIF-1α protein stabilization in hypoxic conditions, an effect insensitive to antioxidant treatment. In human cancers, increased CHCHD4 expression was found to correlate with the hypoxia gene expression signature, increasing tumor grade, and reduced patient survival. Thus, our study identifies a mitochondrial mechanism that is critical for regulating the hypoxic response in tumors.
The Journal of clinical investigation 01/2012; 122(2):600-11. · 15.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: The hypoxia-inducible factor (HIF) family of bHLH-PAS (basic helix-loop-helix per/arnt/sim domain) transcription factors are crucial for responding to changes in cellular oxygen levels. Mitochondria are the powerhouse of oxygen consumption in eukaryotic cells generating chemical energy in the form of adenosine triphosphate (ATP). Recent studies have highlighted the importance of mitochondria for relaying hypoxic signals to regulate HIF function in mammalian cells. In addition, other studies have described a role for multiple HIF-1 transcriptional targets (e.g. pyruvate dehydrogenase kinase 1, BNIP3, lactate dehydrogenase A, complex IV and miRNA210) in controlling cellular oxygen consumption and metabolism by regulating mitochondrial function. In this way, HIF transcriptional activity indirectly controls mitochondrial function, and mitochondria indirectly regulate HIF transcriptional function in response to hypoxia. Despite more than a decade of advances in HIF research, the precise molecular mechanisms for how mitochondria interface with the cellular HIF/oxygen-sensing machinery are yet to be unravelled.