Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE8905 | GEO | 2007/08/29
SECONDARY ACCESSION(S): PRJNA102297
REPOSITORIES: GEO
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Project description:Transcriptional profiling of muscle and liver samples from muscle- and liver-specific AIF knockout mice respectively. Samples obtained from 8 week old, male knockouts, backcrossed 8 times onto the C57Bl6 background are compared to those obtained from littermate control mice. Keywords: disease state analysis, AIF knockout, metabolism
2007-08-29 | GSE8904 | GEO
Project description:Transcriptional profiling of muscle and liver samples from muscle- and liver-specific AIF knockout mice respectively. Samples obtained from 8 week old, male knockouts, backcrossed 8 times onto the C57Bl6 background are compared to those obtained from littermate control mice. Keywords: disease state analysis, AIF knockout, metabolism
2007-08-29 | GSE8901 | GEO
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Project description:Cancer is a major and still increasing cause of death in humans. Most cancer cells have a fundamentally different metabolic profile from that of normal tissue. This shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis, termed Warburg effect, has long been recognized as a paradigmatic hallmark of cancer, supporting the increased biosynthetic demands of tumor cells. Here we show that deletion of apoptosis-inducing factor (AIF) in a KrasG12D-driven mouse lung cancer model resulted in a marked survival advantage, with delayed tumor onset and decreased malignant progression. Mechanistically, Aif deletion leads to oxidative phosphorylation (OXPHOS) deficiency and a switch in cellular metabolism towards glycolysis in non-transformed pneumocytes and at early stages of tumor development. Paradoxically, although Aif-deficient cells exhibited a metabolic Warburg profile, this bioenergetic change resulted in a growth disadvantage of KrasG12D-driven as well as Kras wild-type lung cancer cells. Cell-autonomous re-expression of both wild-type and mutant AIF (displaying an intact mitochondrial, but abrogated apoptotic function) in Aif-knockout KrasG12D mice restored OXPHOS and reduced animal survival to the same level as AIF wild-type mice. In patients with non-small cell lung cancer, high AIF expression was associated with poor prognosis. These data show that AIF-regulated mitochondrial respiration and OXPHOS drive the progression of lung cancer.
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Project description:Type 2 diabetes has become an epidemic disease largely explained by the dramatic increase in obesity in recent years. Mitochondrial dysfunction is suggested as an underlying factor in obesity and type 2 diabetes. In this study, we evaluated changes in oxidative phosphorylation and mitochondrial biogenesis in a new human obesity and type 2 diabetes model, TALLYHO/Jng mice. We hypothesized that the sequence variants identified in the whole genome analysis of TALLYHO/Jng mice would affect oxidative phosphorylation and contribute to obesity and insulin resistant phenotypes. To test this hypothesis, we investigated differences in the expression and activity of oxidative phosphorylation complexes, including the transcription and translation of nuclear- and mitochondrial-encoded subunits and enzymatic activities, in the liver and kidney of TALLYHO/Jng and C57BL/6 J mice. A significant decrease was observed in the expression of nuclear- and mitochondrial-encoded subunits of complex I and IV, respectively, in TALLYHO/Jng mice, which coincided with significant reductions in their enzymatic activities. Furthermore, sequence variants were identified in oxidative phosphorylation complex subunits, a mitochondrial tRNA synthetase, and mitochondrial ribosomal proteins. Our data suggested that the lower expression and activity of oxidative phosphorylation complexes results in the diminished energy metabolism observed in TALLYHO/Jng mice. Sequence variants identified in mitochondrial proteins accentuated a defect in mitochondrial protein synthesis which also contributes to impaired biogenesis and oxidative phosphorylation in TALLYHO/Jng mice. These results demonstrated that the identification of factors contributing to mitochondrial dysfunction will allow us to improve the disease prognosis and treatment of obesity and type 2 diabetes in humans.
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Project description:Delayed neuronal cell death largely contributes to the progressive infarct development and associated functional impairments after cerebral ischemia or brain trauma. Previous studies exposed a key role for the interaction of the mitochondrial protein apoptosis-inducing factor (AIF) and cytosolic cyclophilin A (CypA) in pathways of programmed cell death in neurons in vitro and in vivo. These studies suggested that pro-apoptotic activities of AIF, such as its translocation to the nucleus and subsequent DNA degradation, depend on the physical interaction of AIF with CypA. Hence, this protein complex may represent a new pharmacological target for inhibiting the lethal action of AIF on the brain tissue. In this study, we show that the AIF amino-acid residues 370-394 mediate the protein complex formation of AIF with CypA. The synthetic AIF(370-394) peptide inhibited AIF/CypA complex formation in vitro by binding CypA with a K(D) of 12 ?M. Further, the peptide exerted pronounced neuroprotective effects in a model of glutamate-induced oxidative stress in cultured HT-22 cells. In this model system of AIF-dependent cell death, the AIF(370-394) peptide preserved mitochondrial integrity, as detected by measurements of the mitochondrial membrane potential and quantification of mitochondrial fragmentation. Further, the AIF(370-394) peptide inhibited perinuclear accumulation of fragmented mitochondria, mitochondrial release of AIF to the nucleus and glutamate-induced cell death to a similar extent as CypA-siRNA. These data indicate that the targeting of the AIF-CypA axis is an effective strategy of neuroprotection.
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