Background:The function of the C. elegans mitochondrial uncoupling protein 4 (ceUCP4) has not been characterized. Results: Worms deficient in ceUCP4 displayed hypometabolic phenotypes and complex II dysfunction that corresponded with a significant loss of mitochondrial succinate import. Conclusion: ceUCP4 plays a novel role in the regulation of complex II by controlling succinate transport into mitochondria. Significance: Understanding how extramitochondrial succinate and ceUCP4 regulate complex II-mediated metabolism is critical for understanding the mechanisms of cellular respiration.

Background and purpose: Studies were designed to examine the effects of dietary fats on metabolic effects of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). These effects included hyperthermia, expression of uncoupling protein (UCP1 and 3) in brown adipose tissue or skeletal muscle and plasma free fatty acid (FFA) levels. Experimental approach: Male Sprague-Dawley rats were fed either a high-fat diet (HFD, 60% kcal) or a lower fat isocaloric controlled diet (LFD, 10% kcal) for 28 days before MDMA challenge. Key results: No significant differences were observed between LFD and HFD groups in terms of body weight, plasma thyroxine (T4) levels and expression of brown fat UCP1 or skeletal muscle UCP3 protein. HFD significantly raised levels of circulating FFA and potentiated the thermogenesis induced by MDMA (10 mg kg À1 , s.c.), compared to the effects of the LFD. Moreover, 30 and 60 min after MDMA administration, plasma FFA levels decreased in HFD animals, but were markedly elevated in the LFD group. Conclusions and implications: These results indicate that high-fat feeding regulates MDMA-induced thermogenesis by augmenting the activation of UCP rather than its expression.

Decreased mitochondrial oxidative metabolism is a hallmark bioenergetic characteristic of malignancy that may have an adaptive role in carcinogenesis. By stimulating proton leak, mitochondrial uncoupling proteins (UCP1-3) increase mitochondrial respiration and may thereby oppose cancer development. To test this idea, we generated a mouse model that expresses an epidermal-targeted keratin-5-UCP3 (K5-UCP3) transgene and exhibits significantly increased cutaneous mitochondrial respiration compared with wild type (FVB/N). Remarkably, we observed that mitochondrial uncoupling drove keratinocyte/epidermal differentiation both in vitro and in vivo. This increase in epidermal differentiation corresponded to the loss of markers of the quiescent bulge stem cell population, and an increase in epidermal turnover measured using a bromodeoxyuridine (BrdU)-based transit assay. Interestingly, these changes in K5-UCP3 skin were associated with a nearly complete resistance to chemically-mediated multistage skin carcinogenesis. These data suggest that targeting mitochondrial respiration is a promising novel avenue for cancer prevention and treatment.

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The skeletal musculature is necessary for normal motor functions such as walking or breathing. It accounts for between 35 and 45% of total body weight in humans and is the most energetically demanding tissue in the body. Skeletal muscle is a unique tissue with intricate organizational arrangement, requiring precise regulation of intracellular ions and cooperation by a multitude of cellular proteins. As a result, it also has susceptibilities to a diverse array of toxic insults. Derangements of skeletal muscle function can cause loss of movement, multiorgan involvement and even organismal demise. In addition to direct effects on skeletal muscle, this tissue can also be responsible for damage to distant tissues and organs by release of large intracellular proteins into the vasculature. As a specific topic, skeletal muscle toxicology has been largely absent from the majority of textbooks. However, it represents an important and specific target of a variety of natural and synthetic toxicants. Here we present an overview of skeletal muscle physiology, including tissue architecture, energetic substrate preferences, and function. Laboratory methods and diagnostic observations to be used for investigating skeletal muscle injury in a research and clinical setting are also discussed. Finally, we provide an in‐depth outline of skeletal muscle toxicants arranged according to their proposed mechanism of action.