Biogenesis of the mitochondrial phosphate carrier

The mitochondrial phosphate carrier (PiC) is a member of the family of inner-membrane carrier proteins which are generally synthesized without a cleavable presequence. Surprisingly, the cDNA sequences of bovine and rat PiC suggested the existence of an amino-terminal extension sequence in the precursor of PiC. By expressing PiC in vitro, we found that PiC is indeed synthesized as a larger precursor. This precursor was imported and proteolytically processed by mitochondria, whereby the correct amino-terminus of the mature protein was generated. Import of PiC showed the characteristics of mitochondrial protein uptake, such as dependence on ATP and a membrane potential and involvement of contact sites between mitochondrial outer and inner membranes. The precursor imported in vitro was correctly assembled into the functional form, demonstrating that the authentic import and assembly pathway of PiC was reconstituted when starting with the presequence-carrying precursor. These results are discussed in connection with the recently postulated role of PiC as an import receptor located in the outer membrane

Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle

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Obesity and immune function relationships.

The immunological processes involved in the collaborative defence of organisms are affected by nutritional status. Thus, a positive chronic imbalance between energy intake and expenditure leads to situations of obesity, which may influence unspecific and specific immune responses mediated by humoral and cell mediated mechanisms. Furthermore, several lines of evidence have supported a link between adipose tissue and immunocompetent cells. This interaction is illustrated in obesity, where excess adiposity and impaired immune function have been described in both humans and genetically obese rodents. However, limited and often controversial information exist comparing immunity in obese and non-obese subjects as well as about the cellular and molecular mechanisms implicated. In general terms, clinical and epidemiological data support the evidence that the incidence and severity of specific types of infectious illnesses are higher in obese persons as compared to lean individuals together with the occurrence of poor antibody responses to antigens in overweight subjects. Leptin might play a key role in linking nutritional status with T-cell function. The complexities and heterogeneity of the host defences concerning the immune response in different nutritional circumstances affecting the energy balance require an integral study of the immunocompetent cells, their subsets and products as well as specific and unspecific inducer/regulator systems. In this context, more research is needed to clarify the clinical implications of the alterations induced by obesity on the immune function

Muscle UCP-3 mRNA levels are elevated in weight loss associated with gastrointestinal adenocarcinoma in humans

The mitochondrial uncoupling proteins-2 and -3 are putative mediators of thermogenesis and energy expenditure. We measured the mRNA levels of uncoupling proteins-2 and -3 in skeletal muscle from 12 gastrointestinal adenocarcinoma patients, of whom six had stable weight and six had lost 2–18 kg, and from six healthy controls undergoing elective surgery. Uncoupling proteins-3 mRNA levels were significantly higher in the muscle of the cancer patients with weight loss (2.2±0.47 arbitrary units) compared both with controls (0.39±0.20) and with cancer patients who had not lost weight (0.47±0.23; P<0.02). Uncoupling proteins-2 mRNA levels did not differ significantly between groups. Elevations in muscle uncoupling proteins-3 activity may enhance energy expenditure and this in turn could contribute to tissue catabolism

Role of lipid-mobilising factor (LMF) in protecting tumour cells from oxidative damage

Lipid-mobilising factor (LMF) is produced by cachexia-inducing tumours and is involved in the degradation of adipose tissue, with increased oxidation of the released fatty acids through an induction of uncoupling protein (UCP) expression. Since UCP-2 is thought to be involved in the detoxification of free radicals if LMF induced UCP-2 expression in tumour cells, it might attenuate free radical toxicity. As a model system we have used MAC13 tumour cells, which do not produce LMF. Addition of LMF caused a concentration-dependent increase in UCP-2 expression, as determined by immunoblotting. This effect was attenuated by the β3 antagonist SR59230A, suggesting that it was mediated through a β3 adrenoreceptor. Co-incubation of LMF with MAC13 cells reduced the growth-inhibitory effects of bleomycin, paraquat and hydrogen peroxide, known to be free radical generators, but not chlorambucil, an alkylating agent. There was no effect of LMF alone on cellular proliferation. These results indicate that LMF antagonises the antiproliferative effect of agents working through a free radical mechanism, and may partly explain the unresponsiveness to the chemotherapy of cachexia-inducing tumours. © 2004 Cancer Research UK