. Maternal high-fat diet consumption results in fetal malprogramming predisposing to the onset of metabolic syndrome-like phenotype in adulthood. Am J Physiol Endocrinol Metab 291: E792-E799, 2006. First published May 23, 2006; doi:10.1152/ajpendo.00078.2006.-Chronic consumption of a high-fat (HF) diet by female rats in their postweaning period resulted in significant increases in body weight and plasma levels of insulin, glucose, and triglycerides during pregnancy compared with female rats consuming a standard rodent laboratory chow (LC). On gestational day 21, plasma insulin levels and the insulin secretory response of islets to various secretogogues were significantly increased in HF fetuses. The HF male progeny weaned onto LC (HF/LC) demonstrated increases in body weight from postnatal day 60 onward. In adulthood, HF/LC male rats were significantly heavier than controls, had increased plasma levels of insulin, glucose, free fatty acids, and triglycerides, and demonstrated glucose intolerance. HF/LC male islets secreted increased amounts of insulin in response to low glucose concentrations, but their response to a high glucose concentration was similar to that of LC/LC islets. In another set of experiments, when the male progeny of HF female rats were weaned onto a high-sucrose diet (HF/HSu), their metabolic profile was further worsened. These results indicate that chronic consumption of a HF diet by female rats malprograms the male progeny for glucose intolerance and development of increased body weight in adulthood. The long-term high-fat feeding to female rats employed in this study bears resemblance to the dietary habits in Western societies. The results of this study implicate dietary practices of women in the etiology of the present epidemic of human obesity and related disorders.fat-enriched diet; intrauterine environment; fetal hyperinsulinemia; adult-onset obesity; glucose intolerance OVER THE PAST TWO TO THREE DECADES, the prevalence of obesity has increased steadily and has now reached epidemic proportions in developed countries. In the US alone, more than two-thirds of the adult population have been classified as overweight, with about one-half of them being obese (27). Obesity is a risk factor for the onset of metabolic diseases in adulthood, including type 2 diabetes and cardiovascular diseases (13). More than 80% of people with diabetes are overweight or obese, indicating a close correlation between being overweight and having diabetes (35). It is now recognized that genetics alone cannot explain the unprecedented increase in the number of overweight/obese individuals worldwide. Several environmental factors have been implicated in the etiology of obesity. Hales and Barker (17) coined the term "fetal programming," which was based on data from several epidemiological studies, to demonstrate that metabolic diseases have their origin in early life nutritional experience during gestation and lactation. A nutritional stress/stimulus occurring during the period of fetal development results in adaptiv...

Objective Ketone bodies (KB) are products of fatty acid oxidation and serve as essential fuels during fasting or treatment with the high-fat anti-seizure ketogenic diet (KD). Despite growing evidence that KB exert broad neuroprotective effects, their role in seizure control has not been firmly demonstrated. The major goal of this study was to demonstrate the direct anti-seizure effects of KB and to identify an underlying target mechanism. Methods We studied the effects of both the KD and KB in spontaneously epileptic Kcna1-null mice using a combination of behavioral, planar multi-electrode, and standard cellular electophysiological techniques. Thresholds for mitochondrial permeability transition (mPT) were determined in acutely isolated brain mitochondria. Results KB alone were sufficient to: (1) exert anti-seizure effects in Kcna1-null mice; (2) restore intrinsic impairment of hippocampal long-term potentiation (LTP) and spatial learning-memory defects in Kcna1-null mutants; and (3) raise the threshold for calcium-induced mPT in acutely prepared mitochondria from hippocampi of Kcna1-null animals. Targeted deletion of the cyclophilin D (CypD) subunit of the mPT complex abrogated the effects of KB on mPT, and in vivo pharmacological inhibition and activation of mPT were found to mirror and reverse, respectively, the anti-seizure effects of the KD in Kcna1-null mice. Interpretation The present data reveal the first direct link between mPT and seizure control, and provide a potential mechanistic explanation for the KD. Given that mPT is increasingly being implicated in diverse neurological disorders, our results suggest that metabolism-based treatments and/or metabolic substrates might represent a worthy paradigm for therapeutic development.

Mitochondrial dysfunction following spinal cord injury (SCI) may be critical for the development of secondary pathophysiology and neuronal cell death. Previous studies have demonstrated a loss of mitochondrial bioenergetics at 24 h following SCI. To begin to understand the evolution and study the contribution of mitochondrial dysfunction in pathophysiology of SCI, we investigated mitochondrial bioenergetics in the mid-thoracic region at 6, 12, and 24 h following contusion SCI. It is widely accepted that increased free radical generation plays a critical role in neuronal damage after SCI. Hence, to ascertain the role of free radicals in SCI-induced mitochondrial dysfunction, markers for oxidative damage, including nitrotyrosine (3-NT), lipid peroxidation byproduct (4-hydroxynonenal [HNE]), and protein oxidation (protein carbonyls) were quantified in the same samples of isolated mitochondria during the 24-h time course. The results demonstrate that a significant decline in mitochondrial function begins to occur 12 h post-injury and persists for a least 24 h following SCI. Furthermore, there was a progressive increase in mitochondrial oxidative damage that preceded the loss of mitochondrial bioenergetics, suggesting that free radical damage may be a major mitochondrial secondary injury process. Based on the present results, the temporal profile of mitochondrial dysfunction indicates that interventions targeting mitochondrial oxidative damage and dysfunction may serve as a beneficial pharmacological treatment for acute SCI.

Trichloroethylene, used extensively in industry and the military and a common environmental contaminant, joins other mitochondrial neurotoxins, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and some pesticides, as a risk factor for parkinsonism.

Summary WldS (slow Wallerian degeneration) is a remarkable protein that can suppress Wallerian degeneration of axons and synapses [1] but how it exerts this effect remains unclear [2]. Here, using Drosophila and mouse models, we identify mitochondria as a key site of action for WldS neuroprotective function. Targeting the NAD+ biosynthetic enzyme Nmnat to mitochondria was sufficient to fully phenocopy WldS, and WldS was specifically localized to mitochondria in synaptic preparations from mouse brain. Axotomy of live wild type axons induced a dramatic spike in axoplasmic Ca2+ and termination of mitochondrial movement—WldS potently suppressed both of these events. Surprisingly, WldS also promoted increased basal mitochondrial motility in axons before injury, and genetically suppressing mitochondrial motility in vivo dramatically reduced the protective effect of WldS. Intriguingly, purified mitochondria from WldS mice exhibited enhanced Ca2+ buffering capacity. We propose that the enhanced Ca2+ buffering capacity of WldS+ mitochondria leads to increased mitochondrial motility, suppression of axotomy-induced Ca2+ elevation in axons, and thereby suppression of Wallerian degeneration.

BackgroundPTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca2+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1−/− mice.Methods and FindingsPurified brain mitochondria of Pink1−/− mice showed impaired Ca2+ storage capacity, resulting in increased Ca2+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1−/− mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1−/− mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1−/− mice had increased levels of IL-1β, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1−/− embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-β (NF-κB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1−/− mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting.ConclusionsIncreased mitochondrial Ca2+ sensitivity and JNK activity are early defects in Pink1−/− mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1−/− mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant expression of genes that regulate innate immune responses. While some differentially expressed genes may mitigate neurodegeneration, increased LPS-induced brain cytokine expression and impaired cytokine-induced NF-κB activation may predispose neurons of Pink1−/− mice to inflammation and injury-induced cell death.

Experimental traumatic brain injury (TBI) results in a significant loss of cortical tissue at the site of injury, and in the ensuing hours and days a secondary injury exacerbates this primary injury, resulting in significant neurological dysfunction. The mechanism of the secondary injury is not well understood, but evidence implicates a critical role for mitochondria in this cascade. This mitochondrial dysfunction is believed to involve excitotoxicity, disruption of Ca(2+) homeostasis, production of reactive oxygen species (ROS), ATP depletion, oxidative damage of mitochondrial proteins, and an overall breakdown of mitochondrial bioenergetics. Although oxidative damage occurs following TBI, the identities of proteins undergoing oxidative modification after TBI have not been investigated. In the present study, we utilized the 3-h post-injury controlled cortical impact model of experimental TBI in 20 young adult male Sprague-Dawley rats, coupled with proteomics to identify specific mitochondrial fraction proteins from the cortex and hippocampus that were oxidatively modified after TBI. We identified, from the cortex, pyruvate dehydrogenase, voltage-dependent anion channel, fumarate hydratase 1, ATP synthase, and prohibitin. From the hippocampus, we identified cytochrome C oxidase Va, isovaleryl coenzyme A dehydrogenase, enolase-1, and glyceraldehyde-3-phosphate dehydrogenase as proteins that had undergone oxidative modification following TBI. In addition, we have also shown that, following TBI, there is a reduction in the activities of pyruvate dehydrogenase (PDH), complex I, and complex IV. These findings demonstrate that, following TBI, several proteins involved in mitochondrial bioenergetics are highly oxidatively modified, which may possibly underlie the massive breakdown of mitochondrial energetics and eventual cell death known to occur in this model. The identification of these proteins provides new insights into the mechanisms that take place following TBI and may provide avenues for possible therapeutic interventions after TBI.

Following experimental traumatic brain injury (TBI), a rapid and significant necrosis occurs at the site of injury which coincides with significant mitochondrial dysfunction. The present study is driven by the hypothesis that TBI-induced glutamate release increases mitochondrial Ca(2+)cycling/overload, ultimately leading to mitochondrial dysfunction. Based on this premise, mitochondrial uncoupling during the acute phases of TBI-induced excitotoxicity should reduce mitochondrial Ca(2+) uptake (cycling) and reactive oxygen species (ROS) production since both are mitochondrial membrane potential dependent. In the present study, we utilized a cortical impact model of TBI to assess the potential use of mitochondrial uncouplers (2,4-DNP, FCCP) as a neuroprotective therapy. Young adult male rats were intraperitoneally administered vehicle (DMSO), 2,4-DNP (5 mg/kg), or FCCP (2.5 mg/kg) at 5 min post-injury. All animals treated with the uncouplers demonstrated a significant reduction in the amount of cortical damage and behavioral improvement following TBI. In addition, mitochondria isolated from the injured cortex at 3 or 6 h post-injury demonstrated that treatment with the uncouplers significantly improved several parameters of mitochondrial bioenergetics. These results demonstrate that post-injury treatment with mitochondrial uncouplers significantly (p < 0.01) increases cortical tissue sparing ( approximately 12%) and significantly (p< 0.01) improves behavioral outcome following TBI. The mechanism of neuroprotection most likely involves the maintenance of mitochondrial homeostasis by reducing mitochondrial Ca(2+) loading and subsequent mitochondrial dysfunction. These results further implicate mitochondrial dysfunction as an early event in the pathophysiology of TBI and that targeting acute mitochondrial events can result in long-term neuroprotection and improve behavioral outcome following brain injury.