Uncoupling protein 2 (UCP2) maps to a region on distal mouse chromosome 7 that has been linked to the phenotypes of obesity and type II diabetes. We recently reported that UCP2 expression is increased by high fat feeding in adipose tissue of the A/J strain of mice, which is resistant to the development of dietary obesity. More recently, a third UCP (UCP3) was identified, which is expressed largely in skeletal muscle and brown adipose tissue. The UCP2 and UCP3 genes are located adjacent to one another on mouse chromosome 7. Thus, the roles of these UCPs in both metabolic efficiency and the linkage to obesity and diabetes syndromes is unclear. For this reason, we examined the expression of UCP2 and UCP3 in white adipose tissue and interscapular brown adipose tissue and in gastrocnemius/soleus muscle preparations from the obesity-resistant A/J and C57BL/KsJ (KsJ) strains and the obesity-prone C57BL/6J (B6) mouse strain. In both KsJ and A/J mice, UCP2 expression in white fat was increased ≈2-fold in response to 2 weeks of a high fat diet, but there was no effect of diet on UCP2 levels in B6 mice. In skeletal muscle and in brown fat, neither UCP2 nor UCP3 expression was affected by diet in A/J, B6, or KsJ mice. However, in brown fat, we observed a 2–3-fold increase in the expression of UCP1 in response to dietary fat challenge, which may be related to diet-induced elevations in plasma leptin levels. Together, these results indicate that the consumption of a high fat diet selectively regulates UCP2 expression in white fat and UCP1 expression in brown fat and that resistance to obesity is correlated with this early, selective induction of UCP1 and UCP2 and is not associated with changes in expression of UCP3.

We report here the cloning and functional analysis of a novel homologue of the mitochondrial carriers predominantly expressed in the central nervous system and referred to as BMCP1 (brain mitochondrialcarrier protein-1). The predicted amino acid sequence of this novel mitochondrial carrier indicates a level of identity of 39, 31, or 30%, toward the mitochondrial oxoglutarate carrier, phosphate carrier, or adenine nucleotide translocator, respectively, and a level of identity of 34, 38, or 39% with the mitochondrial uncoupling proteins UCP1, UCP2, or UCP3, respectively. Northern analysis of mouse, rat, or human tissues demonstrated that mRNA of this novel gene is mainly expressed in brain, although it is 10–30-fold less expressed in other tissues.In situ hybridization analysis of brain showed it is particularly abundant in cortex, hippocampus, thalamus, amygdala, and hypothalamus. Chromosomal mapping indicates that BMCP1 is located on chromosome X of mice and at Xq24 in man. Expression of the protein in yeast strongly impaired growth rate. Analysis of respiration of total recombinant yeast or yeast spheroplasts and in particular of the relationship between respiratory rate and membrane potential of yeast spheroplasts revealed a marked uncoupling activity of respiration, suggesting that although BMCP1 sequence is more distant from the uncoupling proteins (UCPs), this protein could be a fourth member of the UCP family.

In mammalian brown adipose tissue, thermogenesis is explained by uncoupling mitochondrial respiration from ATP synthesis. Uncoupling protein‐1 (UCP1) is responsible for this uncoupled state, because it allows proton re‐entry into the matrix and thus dissipates the proton gradient generated by the respiratory chain. Proton transport by UCP1 is regulated negatively by nucleotides and positively by fatty acids. Adrenergic stimulation of brown adipocytes stimulates lipolysis and therefore enhances uncoupling and thermogenesis. Adrenergic stimulation also boosts ucp1 gene transcription. Since retinoic acid also promotes ucp1 gene transcription and its structure makes it a possible activator of UCP1, we hypothesized that retinoic acid, like noradrenaline, could have a dual action and trigger the activity of the protein UCP1 itself. Here we show that retinoic acid strongly increases proton transport by UCP1 in brown adipose tissue mitochondria and that it is much more potent than fatty acids. These data are corroborated with yeast mitochondria where UCP1 was introduced by genetic manipulation. The yeast expression system allows the comparison of the UCP1 with the newly described homologues UCP2 and UCP3. The search for regulators of UCP2 has demonstrated that it is positively regulated by retinoids in a pH‐dependent manner.

Elevated left ventricular mass, a highly heritable trait, is an important risk factor for heart failure and death. Stuart Cook and colleagues genetically dissect a locus in the rat associated with blood-pressure-independent cardiac hypertrophy and identify endonuclease G (ENDOG) as a key regulator of hypertrophy at this locus. They further show that the Endog gene is involved in proper mitochondrial function and is modulated by ERR-α and PGC1α, master regulators of mitochondrial and cardiac function. Loss of function of ENDOG causes impaired mitochondrial respiration and increased production of reactive oxygen species, which may contribute to the observed cardiac hypertrophy. Left ventricular mass (LVM) is a highly heritable trait1 and an independent risk factor for all-cause mortality2. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation3, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood4,5. Unbiased systems genetics approaches in the rat6,7 now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis8 but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function)9,10,11, interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.

Glioblastoma multiforme is resistant to conventional anti-tumoral treatments due to its infiltrative nature and capability of relapse; therefore, research efforts focus on characterizing gliomagenesis and identifying molecular targets useful on therapy. New therapeutic strategies are being tested in patients, such as Histone deacetylase inhibitors (HDACi) either alone or in combination with other therapies. Here two HDACi included in clinical trials have been tested, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), to characterize their effects on glioma cell growth in vitro and to determine the molecular changes that promote cancer cell death. We found that both HDACi reduce glioma cell viability, proliferation and clonogenicity. They have multiple effects, such as inducing the production of reactive oxygen species (ROS) and activating the mitochondrial apoptotic pathway, nevertheless cell death is not prevented by the pan-caspase inhibitor Q-VD-OPh. Importantly, we found that HDACi alter cell cycle progression by decreasing the expression of G2 checkpoint kinases Wee1 and checkpoint kinase 1 (Chk1). In addition, HDACi reduce the expression of proteins involved in DNA repair (Rad51), mitotic spindle formation (TPX2) and chromosome segregation (Survivin) in glioma cells and in human glioblastoma multiforme primary cultures. Therefore, HDACi treatment causes glioma cell entry into mitosis before DNA damage could be repaired and to the formation of an aberrant mitotic spindle that results in glioma cell death through mitotic catastrophe-induced apoptosis.