Comparative analysis of uncoupling protein 4 distribution in various tissues under physiological conditions and during development

Abstract

UCP4 is a member of the mitochondrial uncoupling protein subfamily and one of the three UCPs (UCP2, UCP4, UCP5), associated with the nervous system. Its putative functions include thermogenesis, attenuation of reactive oxidative species (ROS), regulation of mitochondrial calcium concentration and involvement in cell differentiation and apoptosis. Here we investigate UCP4's subcellular, cellular and tissue distribution, using an antibody designed specially for this study, and discuss the findings in terms of the protein's possible functions. Western blot and immunohistochemistry data confirmed that UCP4 is expressed predominantly in the central nervous system (CNS), as previously shown at mRNA level. No protein was found in heart, spleen, stomach, intestine, lung, thymus, muscles, adrenal gland, testis and liver. The reports revealing UCP4 mRNA in kidney and white adipose tissue were not confirmed at protein level. The amount of UCP4 varies in the mitochondria of different brain regions, with the highest protein content found in cortex. We show that UCP4 is present in fetal murine brain tissue as early as embryonic days 12-14 (E12-E14), which coincides with the beginning of neuronal differentiation. The UCP4 content in mitochondria decreases as the age of mice increases. UCP4 preferential expression in neurons and its developmental expression pattern under physiological conditions may indicate a specific protein function, e.g. in neuronal cell differentiation.

Superresolution microscopy reveals spatial separation of UCP4 and F 0 F 1 -ATP synthase in neuronal mitochondria

“…The prevalence of highly energized mitochondria was observed in the periphery of several cells, including cortical neurons (23). UCP4 may be predominantly located in the neuronal cell body (8), where it would dissipate the excessive proton gradient. This location would also better fit UCP4's function in neuronal metabolism (7,27).…”

“…Uncoupling protein 1 (UCP1; thermogenin), a member of the UCP subfamily, is known to dissipate the inner membrane proton gradient for heat production. One of the widely discussed functions for UCP4-another member of the same subfamily that is localized in neurons and neurosensory cells (6)(7)(8)(9)-is the regulation of ROS by decreasing the pmf (10,11). Although there is no unambiguous evidence revealing the exact UCP4 function, it was shown that UCP4 transports protons similar to UCP1 (12).…”

A Ketone Ester Diet Increases Brain Malonyl-CoA and Uncoupling Proteins 4 and 5 while Decreasing Food Intake in the Normal Wistar Rat

“…The striking absence of these effects from ketone body metabolism in brain is most likely due to the increased expression of uncoupling proteins 4 and 5 in brain and the absence of an increase in uncoupling proteins in heart. Uncoupling proteins 4 and 5 have been shown to be expressed primarily in brain (53,54 The effects of ketone metabolism in brain differs from the acute effects of ketone metabolism in heart most significantly by the lack of an increase in mitochondrial reducing power and the absence of a physiologically significant increase in the ⌬G of ATP hydrolysis. These differences are compatible with the observed increase in UCP 4 and 5, which most likely results from the ability of malonyl-CoA to both increase fatty acid synthesis and decrease the transport of fatty acids into the mitochondria where they can undergo ␤ oxidation.…”

Control of Mitochondrial pH by Uncoupling Protein 4 in Astrocytes Promotes Neuronal Survival

“…UCP4 and UCP5 are well expressed in the brain (13,14), and roles in ROS and calcium level regulation (10,15) have been described. In terms of brain cellular localization, immunocytochemistry has revealed that UCP4 is mainly expressed in neurons and less so in astrocytes (16). UCP5 is present in neuronal cell lines (17,18); in the rodent brain, UCP5 expression is observed in the dorsomedial hypothalamic nucleus, hippocampus, paraventricular thalamic nucleus, mediodorsal thalamic nucleus, and ventromedial hypothalamus (13,19).…”