Compromised Energy Production Research Articles

Role of Mitochondrial Dysfunctions in Neurodegenerative Disorders: Advances in Mitochondrial Biology.

Mitochondria, essential organelles responsible for cellular energy production, emerge as a key factor in the pathogenesis of neurodegenerative disorders. This review explores advancements in mitochondrial biology studies that highlight the pivotal connection between mitochondrial dysfunctions and neurological conditions such as Alzheimer's, Parkinson's, Huntington's, ischemic stroke, and vascular dementia. Mitochondrial DNA mutations, impaired dynamics, and disruptions in the ETC contribute to compromised energy production and heightened oxidative stress. These factors, in turn, lead to neuronal damage and cell death. Recent research has unveiled potential therapeutic strategies targeting mitochondrial dysfunction, including mitochondria targeted therapies and antioxidants. Furthermore, the identification of reliable biomarkers for assessing mitochondrial dysfunction opens new avenues for early diagnosis and monitoring of disease progression. By delving into these advancements, this review underscores the significance of understanding mitochondrial biology in unraveling the mechanisms underlying neurodegenerative disorders. It lays the groundwork for developing targeted treatments to combat these devastating neurological conditions.

Mitochondrial dysfunction and oxidative stress in selective fetal growth restriction

IntroductionPlacental dysfunction is the primary cause of selective fetal growth restriction (sFGR), and the specific role of mitochondria remains unclear. This study aims to elucidate mitochondrial functional defects in sFGR placentas and explore the roles of mitochondrial genomic and epigenetic alterations in its pathogenesis. MethodsThe placental villi of MCDA twins with sFGR were collected and the morphology and number of mitochondria were observed by transmission electron microscopy. Meanwhile, the levels of reactive oxygen species (ROS), ATP and oxidative damage markers were assessed. Mitochondrial DNA (mtDNA) copy number detection, targeted sequencing and methylation sequencing were performed. The expression of placental cytochrome c oxidase subunit I (COX I) and mitochondrial long non-coding RNAs (lncRNAs) were evaluated by Western blotting and qPCR. ResultsCompared with placentae from normal fetuses, pronounced mitochondrial damage within cytotrophoblast was revealed in sFGR placentae, alongside augmented mitochondrial number in syncytiotrophoblast. Enhanced oxidative stress in these placentae was evidenced by elevated markers of oxidative damage, accompanied by increased ROS production and diminished ATP generation. In sFGR placentae, a notable rise in mitochondrial copy number and one heterozygous mutation in the MT-RNR2 gene were observed, along with decreased COX Ⅰ levels, increased lncND5, lncND6, lncCyt b, and MDL1 synthesis, and decreased RMRP synthesis. DiscussionFindings collectively confirmed an exacerbation of oxidative stress within sFGR placentae, coinciding with mitochondrial dysfunction, compromised energy production, and ultimately the failure of compensatory mechanisms to restore energy balance, which may result from mutations in the mitochondrial genome and abnormal expression of epigenetic regulatory genes.

Advancing rhodium nanoparticle-based photodynamic cancer therapy: quantitative proteomics and in vivo assessment reveal mechanisms targeting tumor metabolism, progression and drug resistance.

Rhodium nanoparticles have been recently discovered as good photosensitizers with great potential in cancer photodynamic therapy by effectively inducing cytotoxicity in cancer cells under near-infrared laser. This study evaluates the molecular mechanisms underlying such antitumoral effect through quantitative proteomics. The results revealed that rhodium nanoparticle-based photodynamic therapy disrupts tumor metabolism by downregulating key proteins involved in ATP synthesis and mitochondrial function, leading to compromised energy production. The treatment also induces oxidative stress and apoptosis while targeting the invasion capacity of cancer cells. Additionally, key proteins involved in drug resistance are also affected, demonstrating the efficacy of the treatment in a multi-drug resistant cell line. In vivo evaluation using a chicken embryo model also confirmed the effectiveness of the proposed therapy in reducing tumor growth without affecting embryo viability.

Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function.

Pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is expressed mainly in the liver and at low levels in the heart, regulates cholesterol levels by directing low-density lipoprotein receptors to degradation. Studies to determine the role of PCSK9 in the heart are complicated by the close link between cardiac function and systemic lipid metabolism. Here, we sought to elucidate the function of PCSK9 specifically in the heart by generating and analysing mice with cardiomyocyte-specific Pcsk9 deficiency (CM-Pcsk9-/- mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells. Mice with cardiomyocyte-specific deletion of Pcsk9 had reduced contractile capacity, impaired cardiac function, and left ventricular dilatation at 28 weeks of age and died prematurely. Transcriptomic analyses revealed alterations of signalling pathways linked to cardiomyopathy and energy metabolism in hearts from CM-Pcsk9-/- mice vs. wild-type littermates. In agreement, levels of genes and proteins involved in mitochondrial metabolism were reduced in CM-Pcsk9-/- hearts. By using a Seahorse flux analyser, we showed that mitochondrial but not glycolytic function was impaired in cardiomyocytes from CM-Pcsk9-/- mice. We further showed that assembly and activity of electron transport chain (ETC) complexes were altered in isolated mitochondria from CM-Pcsk9-/- mice. Circulating lipid levels were unchanged in CM-Pcsk9-/- mice, but the lipid composition of mitochondrial membranes was altered. In addition, cardiomyocytes from CM-Pcsk9-/- mice had an increased number of mitochondria-endoplasmic reticulum contacts and alterations in the morphology of cristae, the physical location of the ETC complexes. We also showed that acute Pcsk9 silencing in adult cardiomyocyte-like cells reduced the activity of ETC complexes and impaired mitochondrial metabolism. PCSK9, despite its low expression in cardiomyocytes, contributes to cardiac metabolic function, and PCSK9 deficiency in cardiomyocytes is linked to cardiomyopathy, impaired heart function, and compromised energy production.

Alzheimer’s Disease and Parkinson’s Disease: A Nutritional Toxicology Perspective of the Impact of Oxidative Stress, Mitochondrial Dysfunction, Nutrigenomics and Environmental Chemicals

Introduction: Alzheimer’s disease is primarily a dementia-related disorder from progressive cognitive deterioration and memory impairment, while Parkinson’s disease is primarily a movement disorder illness having movement disorder symptoms, bradykinesia (slowness of movements), hypokinesia (reduction of movement amplitude), and akinesia (absence of normal unconscious movements) along with muscle rigidity and tremor at rest. While aging is the main risk factor, epidemiological evidence suggests that the exposure to environmental toxicants, mainly pesticides, metals and solvents could increase the risk of developing neurodegenerative conditions.Oxidative stress in neurodegenerative diseases: Mitochondria function impacts cell respiratory processes, metabolism, energy production, intracellular signaling, free radical production, and apoptosis. In neurodegenerative diseases, mitochondrial dysfunction is associated with a compromised energy production, impaired calcium buffering, activation of proteases and phospholipases, and increased oxidative stress. Oxidative stress induced microglial cells activation, protein aggregation, neuroinflammation and mitochondrial dysfunction lead to neuronal deaths in these disorders.Role of nutrition: Neurodegenerative disease is not curable, but treatment is available to manage the symptoms and slow down the disease progression. The drugs for treating these diseases only reduce the cognitive impairment and behavioral problems, but do not stop the progression of neurodegeneration. Healthy diet, lifestyle improvement and nutraceuticals targeting of oxidative stress, inflammation, abnormal mitochondrial dynamics and the mitochondrial interaction with abnormal disease-related proteins and assessment of impact of environmental contaminants including occupational exposures to pesticides, can be a promising approach in the treatment of neurodegenerative diseases.Conclusion: These innovations can be benchmarked on firm understanding of nutrigenomics and the personalized management of individuals at risk.

Disruption of quercetin metabolism by fungicide affects energy production in honey bees (Apis mellifera)

Cytochrome P450 monooxygenases (P450) in the honey bee, Apis mellifera, detoxify phytochemicals in honey and pollen. The flavonol quercetin is found ubiquitously and abundantly in pollen and frequently at lower concentrations in honey. Worker jelly consumed during the first 3 d of larval development typically contains flavonols at very low levels, however. RNA-Seq analysis of gene expression in neonates reared for three days on diets with and without quercetin revealed that, in addition to up-regulating multiple detoxifying P450 genes, quercetin is a negative transcriptional regulator of mitochondrion-related nuclear genes and genes encoding subunits of complexes I, III, IV, and V in the oxidative phosphorylation pathway. Thus, a consequence of inefficient metabolism of this phytochemical may be compromised energy production. Several P450s metabolize quercetin in adult workers. Docking in silico of 121 pesticide contaminants of American hives into the active pocket of CYP9Q1, a broadly substrate-specific P450 with high quercetin-metabolizing activity, identified six triazole fungicides, all fungal P450 inhibitors, that dock in the catalytic site. In adults fed combinations of quercetin and the triazole myclobutanil, the expression of five of six mitochondrion-related nuclear genes was down-regulated. Midgut metabolism assays verified that adult bees consuming quercetin with myclobutanil metabolized less quercetin and produced less thoracic ATP, the energy source for flight muscles. Although fungicides lack acute toxicity, they may influence bee health by interfering with quercetin detoxification, thereby compromising mitochondrial regeneration and ATP production. Thus, agricultural use of triazole fungicides may put bees at risk of being unable to extract sufficient energy from their natural food.

Mitochondrial genetics and disease.

Mitochondrial disease resulting in reduced bioenergetic output can be due to mutations in either nuclear DNA-encoded or mitochondrial DNA-encoded gene products. We summarize some of the underlying principles of mitochondrial genetics that impact the diagnosis and pathogenesis of mitochondrial disorders. In addition, we present a brief overview of a new frontier in the field, namely, mitochondrial "dynamics," which controls organellar fusion, fission, trafficking, and positioning, and exerts mitochondrial "quality control" by maintaining organellar integrity and viability. Analysis of mutations in gene products associated with this latter area has opened up new vistas in the study of disorders associated with compromised energy production.

The potential role of ozone in ameliorating the age-related biochemical changes in male rat cerebral cortex

Controlled ozone (O(3)) administration is known to promote oxidative preconditioning and, thus, may reverse chronic oxidative stress that accompanies aging. Therefore, the present work was undertaken to study the potential role of O(3) in ameliorating certain age-related biochemical changes represented by impaired activities of inner mitochondrial membrane enzymes, compromised energy production and increased oxidative burden in male rat cerebral cortex. Prophylactic administration of O(3)-O(2) mixture to 3 month-old rats, at an intrarectal dose of 0.6 mg O(3) kg(-1) body weight twice/week for 3 months then once/week until the age of 15 months, normalized reduced glutathione content, adenosine triphosphate/adenosine diphosphate ratio, mitochondrial superoxide dismutase (SOD) and complex IV (cytochrome-c oxidase) activities, improved glutathione redox index (GSHRI), complex I (NADH-ubiquinone oxidoreductase) and mitochondrial nitric oxide synthase (mtNOS) activities, and attenuated the rise in malondialdehyde (MDA) and mitochondrial protein carbonyl levels. On the other hand, therapeutic administration of the same dose of O(3)-O(2) mixture to 14 month-old rats three times/week for 1 month, reduced mitochondrial protein carbonyl level only. Other favorable effects, including normalization of Na,K-adenosine triphosphatase (Na,K-ATPase) activity and reduction in lipofuscin level in the prophylactic group, as well as improvement in mitochondrial SOD and complex I activities with a decrease in total MDA level in the therapeutic group, were comparable to the effects observed in the corresponding O(2)-treated control groups. In conclusion, the present study revealed that prophylactic administration of O(3)-O(2) mixture provided better amelioration of age-related cerebrocortical alterations by combining the advantages of both O(3) and O(2) therapies.

Mitochondrial diseases: Translation matters

Mitochondrial diseases comprise a heterogeneous group of disorders characterized by compromised energy production. Since the early days of mitochondrial medical genetics, it has been known that these can be caused by defects in mitochondrial protein synthesis. However, only in recent years have we begun to develop a broader picture of the array of proteins required for mitochondrial translation. With this new knowledge has come the realization that there are many more neurological and other, diseases attributable to impaired mitochondrial translation than previously thought. Perturbation of any part of this intricate machinery, from the primary sequence of transfer or ribosomal RNAs, to the proteolytic processing of ribosomal proteins, can cause mitochondrial dysfunction and disease. In this review we discuss the current understanding of the mechanisms and factors involved in mammalian mitochondrial translation, and the diverse pathologies resulting when it malfunctions. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'.

Proteome and Metabolome Alterations in Heart and Liver Indicate Compromised Energy Production During Sepsis

During the course of sepsis, heart and liver dysfunction occurs in 20-30 % of patients. Both septic cardiomyopathy and septic liver dysfunction have a high mortality and the underlying molecular pathophysiology remains unclear. The present study investigated changes in both cardiac and liver protein expression after cecal ligature and puncture (CLP) in a model of rat sepsis during a post-induction time course of 12, 24, and 48 hours. After approval by the local institutional review board, 62 male Wistar rats were investigated and assigned to three sham groups (n=16) and three sepsis groups (n=46). Rats of the sepsis groups and control groups were analyzed at specific time points after sepsis induction. Sepsis was induced by CLP and both heart and liver were removed after decapitation and prepared for proteomics. 2D-gel electrophoresis (2D-GE) and mass spectrometry (MS) as well as bioinformatic network pathway analysis (Ingenuity Pathways Analysis, IPA) were used to identify changes in protein expression between septic and non-septic samples. N=27 rats of the sepsis group died (mortality 59 %) and no rat of the sham group died. More than 1,100 proteins could be discriminated with the proteomic method in both organs, of which 12 and 13 proteins were significantly regulated in heart and liver, respectively. 82 % of the cardiac proteins could be associated with mitochondrial function. Both heart and liver proteins were primarily down-regulated in the course of sepsis. IPA associated the sets of differentially regulated proteins with proteins of heart and liver with compromised energy production. Sepsis induced significant alterations in the cardiac and liver proteome at 12, 24, and 48 hours after sepsis induction. Differentially regulated proteins of both organs mainly play a role in energy production. The diverse protein regulation indicates metabolic derangement and severely compromised cellular energy production following sepsis. Here, protein alterations may reflect septic organ dysfunction.

Mechanisms of ethanol-induced degeneration in the developing, mature, and aging cerebellum

The adverse effects of acute and chronic ethanol exposure on cerebellar functions have been acknowledged for decades, in terms of impaired control of movement and balance. In addition to the motor impairment, cerebellar degeneration has recently been shown to contribute to distinct neuropsychological deficits in chronic alcoholics, as well as in children with prenatal ethanol exposure. The basic mechanisms underlying these ethanol-induced functional alterations and the related neuropathology in the cerebellum have mostly been clarified only recently. These mechanisms include: (i) excitotoxicity; (ii) dietary factors, especially thiamine depletion; (iii) glial abnormalities; (iv) changes in growth factors; (v) apoptotic mechanisms; (vi) oxidative stress; and (vii) compromised energy production. Although these mechanisms widely apply not only to the mature cerebellum, but also to the developing and the aging cerebella, the developing and the aged cerebellum have some special characteristics, which may make them even more vulnerable to ethanol-induced degeneration. These special instances will be discussed along with the general mechanisms of ethanol-induced cerebellar degeneration.

Liver Regeneration Is Suppressed in Small-for-Size Liver Grafts after Transplantation: Involvement of c-Jun N-terminal Kinase, Cyclin D1, and Defective Energy Supply

Small-for-size liver grafts have decreased survival compared to full-size grafts. This study investigated mechanisms of suppression of liver regeneration in small-for-size grafts. Rat liver explants were reduced in size to 50% and implanted into recipients of different body weights, resulting in graft weight/standard liver weights of approximately 50% (half-size) and approximately 25% (quarter-size). Hepatic cellular 5-bromo-2'-deoxyuridine (BrdU) incorporation increased from 0.2% after sham operation to 2%, 18%, and 1.2% in full-size, half-size, and quarter-size grafts, respectively. Graft weight did not increase in full- and quarter-size grafts but increased 40% in half-size grafts. By contrast, apoptosis remained low (< or =0.7%) and stem cells did not increase in all conditions. Phospho-c-Jun increased 27-fold in half-size grafts but only sevenfold in quarter-size grafts. Activating protein-1 activation increased 14-fold in half-size grafts but only fivefold in quarter-size grafts. Cyclin D1 (CyD1), which was barely detectable in full- and quarter-size grafts, increased 8.3-fold in half-size grafts. Adenosine 5'-triphosphate (ATP) per gram tissue decreased 70% in quarter-size grafts. Treatment of quarter-size grafts with radical scavenging C. sinenesis polyphenols (20 microg/ml) increased BrdU labeling and weight gain to 35% and 56%, respectively, reversed inhibition of CyD1 expression, c-Jun phosphorylation, and AP-1 activation in quarter-size grafts compared to half-size grafts, and restored ATP levels to 75%. Liver regeneration is stimulated in half-size grafts but suppressed in quarter-size grafts. Defective liver regeneration in small grafts is associated with an inhibition of the c-Jun N-terminal kinase/c-Jun and CyD1 pathways and compromised energy production.

AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs?

In Alzheimer's disease, age-related cellular changes such as compromised energy production and increased radical formation are worsened by the presence of AGEs as additional, AD specific stress factors. Intracellular AGEs (most likely derived from methylglyoxal) crosslink cytoskeletal proteins and render them insoluble. These aggregates inhibit cellular functions including transport processes and contribute to neuronal dysfunction and death. Extracellular AGEs, which accumulate in ageing tissue (but most prominently on long-lived protein deposits like the senile plaques) exert chronic oxidative stress on neurons. In addition, they activate glial cells to produce free radicals (superoxide and NO) and neurotoxic cytokines such as TNF-alpha. Drugs, which inhibit the formation of AGEs by specific chemical mechanisms (AGE-inhibitors), including aminoguanidine, carnosine, tenilsetam, OPB-9195 and pyridoxamine, attenuate the development of (AGE-mediated) diabetic complications. Assuming that 'carbonyl stress' contributes significantly to the progression of Alzheimer's disease, AGE-inhibitors might also become interesting novel therapeutic drugs for treatment of AD.