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Excess dietary fructose is a major public health concern, yet little is known about its influence on offspring development and later-life disease when consumed in excess during pregnancy. To determine whether increased maternal fructose intake could have long-term consequences on offspring health, we investigated the effects of 10% w/v fructose water intake during preconception and pregnancy in guinea pigs. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD; providing 16% of total daily caloric intake) ad libitum 60 days prior to mating and throughout gestation. Dietary interventions ceased at day of delivery. Offspring were culled at day 21 (D21) (weaning) and at 4 months (4 M) (young adult). Fetal exposure to excess maternal fructose intake significantly increased male and female triglycerides at D21 and 4 M and circulating palmitoleic acid and total omega-7 through day 0 (D0) to 4 M. Proteomic and functional analysis of significantly differentially expressed proteins revealed that FD offspring (D21 and 4 M) had significantly increased mitochondrial metabolic activities of β-oxidation, electron transport chain (ETC) and oxidative phosphorylation and reactive oxygen species production compared to the CD offspring. Western blotting analysis of both FD offspring validated the increased protein abundances of mitochondrial ETC complex II and IV, SREBP-1c and FAS, whereas VDAC1 expression was higher at D21 but lower at 4 M. We provide evidence demonstrating offspring programmed hepatic mitochondrial metabolism and de novo lipogenesis following excess maternal fructose exposure. These underlying asymptomatic programmed pathways may lead to a predisposition to metabolic dysfunction later in life.

Shuxuetong injection composed of leech (Hirudo nipponica Whitman) and earthworm (Pheretima aspergillum) has been used for the clinical treatment of acute stroke for many years in China. However, the precise neuroprotective mechanism of Shuxuetong injection remains poorly understood. Here, cerebral microvascular endothelial cells (bEnd.3) were incubated in glucose-free Dulbecco's modified Eagle's medium containing 95% N2/5% CO2 for 6 hours, followed by high-glucose medium containing 95% O2 and 5% CO2 for 18 hours to establish an oxygen-glucose deprivation/reperfusion model. This in vitro cell model was administered Shuxuetong injection at 1/32, 1/64, and 1/128 concentrations (diluted 32-, 64-, and 128-times). Cell Counting Kit-8 assay was used to evaluate cell viability. A fluorescence method was used to measure lactate dehydrogenase, and a fluorescence microplate reader used to detect intracellular reactive oxygen species. A fluorescent probe was also used to measure mitochondrial superoxide production. A cell resistance meter was used to measure transepithelial resistance and examine integrity of monolayer cells. The fluorescein isothiocyanate-dextran test was performed to examine blood-brain barrier permeability. Real-time reverse transcription polymerase chain reaction was performed to analyze mRNA expression levels of tumor necrosis factor alpha, interleukin-1β, interleukin-6, and inducible nitric oxide synthase. Western blot assay was performed to analyze expression of caspase-3, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, occludin, vascular endothelial growth factor, cleaved caspase-3, B-cell lymphoma 2, phosphorylated extracellular signal-regulated protein kinase, extracellular signal-regulated protein kinase, nuclear factor-κB p65, I kappa B alpha, phosphorylated I kappa B alpha, I kappa B kinase, phosphorylated I kappa B kinase, claudin-5, and zonula occludens-1. Our results show that Shuxuetong injection increases bEnd.3 cell viability and B-cell lymphoma 2 expression, reduces cleaved caspase-3 expression, inhibits production of reactive oxygen species and mitochondrial superoxide, suppresses expression of tumor necrosis factor alpha, interleukin-1β, interleukin-6, inducible nitric oxide synthase mRNA, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, markedly increases transepithelial resistance, decreases blood-brain barrier permeability, upregulates claudin-5, occludin, and zonula occludens-1 expression, reduces nuclear factor-κB p65 and vascular endothelial growth factor expression, and reduces I kappa B alpha, extracellular signal-regulated protein kinase 1/2, and I kappa B kinase phosphorylation levels. Overall, these findings suggest that Shuxuetong injection has protective effects on brain microvascular endothelial cells after oxygen-glucose deprivation/reperfusion. Moreover, its protective effect is associated with reduction of mitochondrial superoxide production, inhibition of the inflammatory response, and inhibition of vascular endothelial growth factor, extracellular signal-regulated protein kinase 1/2, and the nuclear factor-κB p65 signaling pathway.

Background： Tumor necrosis factor-α （TNF-α） plays an important role in progressive contractile dysfunction in several cardiac diseases. The cytotoxic effects of TNF-α are suggested to be partly mediated by reactive oxygen species （ROS）- and mitochondria-dependent apoptosis. Glucagon-like peptide- 1 （GLP-1） or its analogue exhibits protective effects on the cardiovascular system. The objective of the study was to assess the effects ofexenatide, a GLP- 1 analogue, on oxidative stress, and apoptosis in TNF-α-treated cardiomyocytes in vitro. Methods： Isolated neonatal rat cardiomyocytes were divided into three groups： Control group, with cells cultured in normal conditions without intervention; TNF-α group, with cells incubated with TNF-α （40 ng/ml） for 6, 12, or 24 h without pretreatment with exenatide; and exenatide group, with cells pretreated with exenatide （100 nmol/L） 30 mins before TNF-α （40 ng/ml） stimulation. We evaluated apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling （TUNEL） assay and flow cytometry, measured ROS production and mitochondrial membrane potential （MMP） by specific the fluorescent probes, and assessed the levels of proteins by Western blotting for all the groups. Results： Exenatide pretreatment significantly reduced cardiomyocyte apoptosis as measured by flow cytometry and TUNEL assay at 12 h and 24 h. Also, exenatide inhibited excessive ROS production and maintained MMP. Furthermore, declined cytochrome-c release and cleaved caspase-3 expression and increased bcl-2 expression with concomitantly decreased Bax activation were observed in exenatide-pretreated cultures. Conclusion： These results suggested that exenatide exerts a protective effect on cardiomyocytes, preventing TNF-α-induced apoptosis; the anti-apoptotic effects may be associated with protection ofmitochondrial function.

Mitochondria are the major source of intercellular bioenergy in the form of ATP. They are necessary for cell survival and play many essential roles such as maintaining calcium homeostasis, body temperature, regulation of metabolism and apoptosis. Mitochondrial dysfunction has been observed in variety of diseases such as cardiovascular disease, aging, type 2 diabetes, cancer and degenerative brain disease. In other words, the interpretation and regulation of mitochondrial signals has the potential to be applied as a treatment for various diseases caused by mitochondrial disorders. In recent years, mitochondrial transplantation has increasingly been a topic of interest as an innovative strategy for the treatment of mitochondrial diseases by augmentation and replacement of mitochondria. In this review, we focus on diseases that are associated with mitochondrial dysfunction and highlight studies related to the rescue of tissue-specific mitochondrial disorders. We firmly believe that mitochondrial transplantation is an optimistic therapeutic approach in finding a potentially valuable treatment for a variety of mitochondrial diseases.

Mitochondria calcium is a double-edged sword. While low levels of calcium are essential to maintain optimal rates of ATP production, extreme levels of calcium overcoming the mitochondrial calcium retention capacity leads to loss of mitochondrial function. In moderate amounts, however, ATP synthesis rates are inhibited in a calcium-titratable manner. While the consequences of extreme calcium overload are well-known, the effects on mitochondrial function in the moderately loaded range remain enigmatic. These observations are associated with changes in the mitochondria ultrastructure and cristae network. The present mini review/perspective follows up on previous studies using well-established cryo–electron microscopy and poses an explanation for the observable depressed ATP synthesis rates in mitochondria during calcium-overloaded states. The results presented herein suggest that the inhibition of oxidative phosphorylation is not caused by a direct decoupling of energy metabolism via the opening of a calcium-sensitive, proteinaceous pore but rather a separate but related calcium-dependent phenomenon. Such inhibition during calcium-overloaded states points towards mitochondrial ultrastructural modifications, enzyme activity changes, or an interplay between both events.

APOE ε4 allele (ApoE4) is the primary genetic risk factor for sporadic Alzheimer’s disease (AD), expressed in 40–65% of all AD patients. ApoE4 has been associated to many pathological processes possibly linked to cognitive impairment, such as amyloid-β (Aβ) and tau pathologies. However, the exact mechanism underlying ApoE4 impact on AD progression is unclear, while no effective therapies are available for this highly debilitating neurodegenerative disorder. This review describes the current knowledge of ApoE4 interaction with mitochondria, causing mitochondrial dysfunction and neurotoxicity, associated with increased mitochondrial Ca2+ and reactive oxygen species (ROS) levels, and it effects on mitochondrial dynamics, namely fusion and fission, and mitophagy. Moreover, ApoE4 translocates to the nucleus, regulating the expression of genes involved in aging, Aβ production, inflammation and apoptosis, potentially linked to AD pathogenesis. Thus, novel therapeutical targets can be envisaged to counteract the effects induced by ApoE4 in AD brain.

IntroductionAlcohol use disorder (AUD) is a specific psychological state induced by repeated heavy drinking, and withdrawal symptoms such as anxiety are closely related to relapse after withdrawal. While neuronal damage caused by alcohol is considered a significant precipitating factor for withdrawal-induced anxiety, the underlying molecular mechanisms remain unclear.MethodsIn this study, we established a mouse model of alcohol withdrawal through 3 months of chronic ethanol exposure (CEE) followed by withdrawal. Mice were treated with semaglutide (0.03 mg/kg) via intraperitoneal injection and subjected to behavioral, biochemical, and morphological analyses.ResultsOur results demonstrate that the glucagon-like peptide-1 receptor (GLP-1R) agonist semaglutide alleviates anxiety-like behaviors in CEE withdrawal mice and reverses the downregulation of GLP-1R and its downstream effector CREB in the mitochondria of prefrontal cortex (PFC) neurons. Enhancing the GLP-1R/CREB pathway regulates mitochondrial quality control, including fission, fusion, and mitophagy, to maintain mitochondrial function and ameliorate synaptic impairment.DiscussionThese findings suggest that activation of GLP-1R ameliorates alcohol withdrawal-induced anxiety-like behaviors by regulating neuronal mitochondrial function, providing a potential therapeutic target for AUD.

IntroductionHeart Failure (HF) carries significant mortality and morbidity, especially due to comorbidities such as Atrial Fibrillation (AF). Previous work illustrates that mitochondrial dysfunction underpins the pathophysiology of both HF and AF, including decreased Adenosine TriPhosphate (ATP) production, Ca2+ mishandling, oxidative stress and elevated apoptosis. In addition to these problems, recent work suggests the Mitochondrial Permeability Transition Pore (MPTP) in ventricular cardiomyocytes may become sensitised to Ca2+ during HF, leading to increased apoptosis. Nevertheless, the role of mitochondrial dysfunction has not been investigated in the atria. In this study, we investigated the role of Ca2+ sensitivity of the MPTP and mitochondrial aerobic capacity in atrial muscle of the failing heart.MethodsRight atrial appendage and right ventricular free wall were dissected from 15 sheep representing an ovine model of tachycardia-induced HF. The tissue was subsequently homogenized and differentially centrifuged, yielding isolated mitochondria. Respiratory function was measured using a respirometer, with the electron transport system (ETS) selectively probed through addition of various substrates stimulating differing ETS complexes. A Calcium Retention Capacity (CRC) assay determined MPTP Ca2+ sensitivity, which involved Ca2+ titrations onto isolated mitochondria containing a Ca2+-sensitive fluorescent dye. An increase in fluorescence marked MPTP opening.ResultsAerobic capacity was not affected by HF, but an increase in ventricular leak respiration was statistically significant (p=0.0140). HF reduced atrial mitochondrial efficiency by 68% (p=0.0063) but did not affect maximal mitochondrial respiration. There was no significant effect of HF or tissue-type on MPTP Ca2+ sensitivity and mitochondrial Ca2+ buffering capacity.ConclusionOur data suggests HF affects atrial and ventricular mitochondrial respiratory function asymmetrically, with HF affecting atrial mitochondrial efficiency and ventricular leak respiration. The COVID-19 pandemic hindered this research project; however, it provides rationale on the unequal effect of HF on mitochondrial function across the atria and ventricle. Future research should therefore consider incorporating atrial samples when assessing potential HF therapies.Conflict of InterestNil

Mitochondria control cellular fate by various mechanisms and are key drivers of cellular metabolism. Although the main function of mitochondria is energy production, they are also involved in cellular detoxification, cellular stabilization, as well as control of ketogenesis and glucogenesis. Conditions like neurodegenerative disease, insulin resistance, endocrine imbalances, liver and kidney disease are intimately linked to metabolic disorders or inflexibility and to mitochondrial dysfunction. Mitochondrial dysfunction due to a relative lack of micronutrients and substrates is implicated in the development of many chronic diseases. l-carnitine is one of the key nutrients for proper mitochondrial function and is notable for its role in fatty acid oxidation. l-carnitine also plays a major part in protecting cellular membranes, preventing fatty acid accumulation, modulating ketogenesis and glucogenesis and in the elimination of toxic metabolites. l-carnitine deficiency has been observed in many diseases including organic acidurias, inborn errors of metabolism, endocrine imbalances, liver and kidney disease. The protective effects of micronutrients targeting mitochondria hold considerable promise for the management of age and metabolic related diseases. Preventing nutrient deficiencies like l-carnitine can be beneficial in maintaining metabolic flexibility via the optimization of mitochondrial function. This paper reviews the critical role of l-carnitine in mitochondrial function, metabolic flexibility and in other pathophysiological cellular mechanisms.