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Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression.

ABSTRACT: Increased expression of the regulatory subunit of HIFs (HIF-1? or HIF-2?) 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-1? 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-1? 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.

SUBMITTER: Yang J

PROVIDER: S-EPMC3266784 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression.

Yang Jun J Staples Oliver O Thomas Luke W LW Briston Thomas T Robson Mathew M Poon Evon E Simões Maria L ML El-Emir Ethaar E Buffa Francesca M FM Ahmed Afshan A Annear Nicholas P NP Shukla Deepa D Pedley Barbara R BR Maxwell Patrick H PH Harris Adrian L AL Ashcroft Margaret M

The Journal of clinical investigation 20120103 2

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 splice ...[more]

PMID: 22214851

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Project description:In recent years, increasing levels of dissolved carbon dioxide in seawater have led to an increase of ocean acidification (OA), which constitutes a major threat to marine ecosystems. As an important economically marine bivalve, Mactra veneriformis is highly susceptible to ocean acidification. In this study, we recorded and observed the mortality rate, oxygen consumption rate and ammonia excretion rate of different shell colour groups of M. veneriformis under the stress of ocean acidification (pH=7.6), and conducted transcriptome analysis of the mantle tissues of M. veneriformis with white and purple shell colours in the acidified group (pH=7.6) and the control group (pH=8.1) under the two conditions, which showed that there was a significant difference in mortality rate between the acidified group and the control group at day 30, but there was a significant difference in mortality rate between the white colors group and the purple colors group at day 30, which was not significant. The results showed that there was a significant difference in mortality between the acidified and control groups at day 30, but the difference in mortality between the white and purple shell colour groups at day 30 was not significant. In the transcriptome analysis, fatty acid synthase gene was up-regulated in two shell colours of M. veneriformis under acidification stress, which may be a molecular compensatory mechanism to reduce the susceptibility of organisms to oxidative damage of lipids; tyrosinase gene was up-regulated, which may be a compensatory mechanism of Tyr's regulatory mechanism to the formation of shell damages under acidification; carbonic anhydrase gene was up-regulated in the purple group of M. veneriformis under acidification stress, which may be a compensatory mechanism for the acidity of M. veneriformis to cope with environmental stress; the white group of M. veneriformis under acidification stress was up-regulated. The carbonic anhydrase gene was up-regulated in the purple group under acidification stress, which may be an acidity compensation mechanism of M. veneriformis in response to the environmental stress.

Dataset Information

Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression.

Publications

Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression.

Similar Datasets

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