Impaired Mitochondrial Function Research Articles

Mitochondrial function in patients affected with fibromyalgia syndrome is impaired and correlates with disease severity

Fibromyalgia is a musculoskeletal syndrome characterized by chronic widespread pain that is often associated with systemic manifestations. Since mitochondria are the main source of cellular energy, we hypothesized that fibromyalgia syndrome (FMS) could be linked to mitochondrial impairment. Aim was to study mitochondrial dysfunction in peripheral blood mononuclear cells isolated from 50 patients with primary FMS and 20 apparently healthy controls. Although no differences in mitochondrial basal respiration were observed between patients with primary FMS and healthy controls, a lower median bioenergetic health index (BHI; − 22.1%, p = 0.03), a proxy of mitochondrial function, was found in patients. According to fibromyalgia severity score (FSS), a composite of widespread pain index and symptom severity scale, a lower median BHI (− 18.7%) was found in patients with a FSS ≥ 20 compared to those with a FSS < 20. Negative moderate correlations were found only between BHI and FSS (r = − 0.36) and widespread pain index (r = − 0.38). We demonstrated that patients with FMS had an impaired mitochondrial function. Additionally, we found a mild correlation between the widespread pain index and the BHI, possibly indicating that the altered mitochondrial function, in these patients, narrows musculoskeletal rather than central nervous system involvement.

Nicotinamide riboside targets mitochondrial unfolded protein response to reduce alcohol-induced damage in Kupffer cells.

The pathogenesis of alcohol-related liver disease (ALD) is closely linked to mitochondrial dysfunction and impaired cellular energy metabolism. In this study, we explored how ethanol triggers inflammation, oxidative stress, and mitochondrial dysfunction in Kupffer cells, i.e.hepatic resident macrophages, primarily focusing on the mitochondrial unfolded protein response (UPRmt) using immortalized mouse Kupffer cells (ImKCs) and mouse primary KCs. The UPRmt is a cellular defense mechanism activated in response to the perturbation of mitochondrial proteostasis to maintain mitochondrial integrity and function by upregulating the expression of mitochondrial chaperones and proteases. We also determined whether nicotinamide riboside (NR), a NAD+ precursor, could mitigate ethanol-triggered cellular damage. When ImKCs were exposed to 80 mm ethanol for 72 h, they displayed inflammation, oxidative stress, and impaired mitochondrial function with decreased mitochondrial content and deformed mitochondrial crista structure. NR, however, counteracted the effects of ethanol. Furthermore, ethanol increased mRNA and protein levels of UPRmt genes, such as mitochondrial chaperones and proteases, which were attenuated by NR. Notably, the ethanol-induced shift in the entry of activating transcription factor 5 (ATF5), a putative transcriptional regulator of UPRmt, to the nucleus from the mitochondria was abolished by NR. The induction of UPRmt genes by ethanol was significantly repressed when Atf5 was knocked down, indicating the role of ATF5 in the induction of UPRmt genes in ImKCs exposed to ethanol. We also confirmed the induction of UPRmt gene expression in mouse and human livers exposed to alcohol. Our findings demonstrate the ability of NR to alleviate ethanol-induced oxidative stress, inflammation, and mitochondrial dysfunction, partly by modulating the ATF5-dependent UPRmt pathway in ImKCs, suggesting its potential for ALD therapy. © 2024 The Pathological Society of Great Britain and Ireland.

The effect of trimetazidine on cardiac haemodynamics and mitochondrial function in wild-type transthyretin amyloidosis.

Wild-type transthyretin cardiac amyloidosis (ATTRwt) is a cardiomyopathy causing myocardial hypoperfusion and impaired cardiac mitochondrial function. Trimetazidine is an antianginal agent used in patients with stable angina pectoris, which improves cardiac contractility and mitochondrial function. The aim of the study was to investigate the effect of trimetazidine on invasive haemodynamics and cardiac mitochondrial function in ATTRwt. In a randomized, double-blind, placebo-controlled, crossover trial, 22 patients with ATTRwt received 4weeks of trimetazidine and placebo in randomized order. After each treatment period followed examinations with endomyocardial biopsies taken for high-resolution respirometry and right heart catheterization at rest and during a cardiopulmonary exercise test. The primary endpoint was mean pulmonary artery wedge pressure (mPAWP) during peak exercise. The secondary endpoint was cardiac mitochondrial oxidative phosphorylation capacity. Exploratory endpoints were echocardiographic parameters, cardiac biomarker levels and quality of life. Trimetazidine did not significantly reduce mPAWP during peak exercise (31±12 vs. 31±13mmHg, P=0.61) or improve the cardiac mitochondrial oxidative phosphorylation capacity (73.4±7.7 vs. 75.3±7.7pmol O2/(mg*s), P=0.81) compared with placebo, nor did treatment with trimetazidine improve ejection fraction (P=0.93), global longitudinal strain (P=0.23), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P=0.92) or the patients' quality of life (P=0.98). In ATTRwt, treatment with trimetazidine did not improve mPAWP or cardiac mitochondrial oxidative phosphorylation capacity compared with placebo.

Protective Effects of Antcin H Isolated from Antrodia cinnamomea Against Neuroinflammation in Huntington's Disease via NLRP3 Inflammasome Inhibition.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. When the CAG repeat exceeds 36, it results in the accumulation of the mutant HTT (mHTT) protein in neurons and glial cells. Key pathological mechanisms in HD include excitotoxicity, energy dysfunction, impaired mitochondrial function, increased oxidative stress, and neuroinflammation. The NLRP3 inflammasome is a multimeric protein complex element of NLRP3, ASC, and caspase-1, which regulates interleukin (IL)-1β and IL-18 secretion. The NLRP3 inflammasome plays an important role in inflammatory reactions and is involved in the pathogenesis of several neurodegenerative diseases. We have previously demonstrated high NLRP3 inflammasome expression levels in the striatum of R6/2 mice (a transgenic HD mouse model). Systematic administration of an NLRP3 inhibitor (MCC950) to R6/2 mice suppressed the NLRP3 inflammasome, decreased IL-1β and reactive oxygen species production, and reduced neuronal toxicity, suggesting protective effects against HD. Antrodia cinnamomea is an indigenous medicinal fungus in Taiwan, which shows diverse medicinal and pharmacological activities, but its effects in HD are not well understood. Herein, we report that systematic administration of Antcin-H isolated from A. cinnamomea to R6/2 mice suppressed the NLRP3 inflammasome, IL-1β production, and reduced neuronal toxicity. Most importantly, oral administration of Antcin-H reduced disease progression by increasing neuronal survival, reducing neuroinflammation during an extended lifespan, and improving motor dysfunction in R6/2 mice. Taken together, our data suggest that Antcin-H has therapeutic potential for treating HD.

5'tiRNA-33-CysACA-1 promotes septic cardiomyopathy by targeting PGC-1α-mediated mitochondrial biogenesis

BackgroundWe revealed for the first time that the expression of 158 tRNA-derived small RNAs (tsRNAs) was altered in septic cardiomyopathy (SCM) by microarray analysis, and we selected 5'tiRNA-33-CysACA-1, which was the most significantly up-regulated, as a representative to explore the roles and mechanisms of tsRNAs in SCM. MethodsWe constructed a sepsis model by cecum ligation and puncture (CLP) in mice and detected the expression of 5'tiRNA-33-CysACA-1 using quantitative real-time PCR (qRT-PCR). The supernatant generated after LPS stimulation of macrophages was used as the conditional medium (CM) to stimulate H9C2 and established the injured cell model. CCK-8 and LDH release assays were used to detect cell viability and cell death. Mitochondrial membrane potential (MMP), ATP production, ROS production, and Mitotracker Red mitochondrial morphology were assayed to assess mitochondrial function. Expression of mRNA for molecules related to the mitochondrial quality control system was verified by qRT-PCR. The mechanism by which 5'tiRNA-33-CysACA-1 regulates peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) expression was examined by western blot, mRNA stability analysis, and rescue experiments. ResultsExpression of 5'tiRNA-33-CysACA-1 was elevated in cardiac tissue and H9C2 cells during septic myocardial injury. Stimulation of the CM resulted in cardiomyocyte injury and impaired mitochondrial function. Transfection of 5'tiRNA-33-CysACA-1 mimic in CM further downregulated PGC-1α expression, inhibited mitochondrial biogenesis thereby impairing mitochondrial function and leading to decreased cardiomyocyte activity and increased cell death. In contrast, transfection of the inhibitor ameliorated the above biological processes. In addition, mRNA stability assay and bioinformatics analysis showed that 5'tiRNA-33-CysACA-1 led to a decrease in the stability of PGC-1α mRNA, which in turn downregulated the expression of PGC-1α and promoted the development of SCM. Conclusions5'tiRNA-33-CysACA-1 expression is upregulated in SCM and inhibits mitochondrial biogenesis by targeting PGC-1α and decreasing the stability of PGC-1α mRNA, leading to mitochondrial dysfunction and promoting the development of SCM.

Impact of ageing and disuse on neuromuscular junction and mitochondrial function and morphology: Current evidence and controversies.

Inactivity and ageing can have a detrimental impact on skeletal muscle and the neuromuscular junction (NMJ). Decreased physical activity results in muscle atrophy, impaired mitochondrial function, and NMJ instability. Ageing is associated with a progressive decrease in muscle mass, deterioration of mitochondrial function in the motor axon terminals and in myofibres, NMJ instability and loss of motor units. Focusing on the impact of inactivity and ageing, this review examines the consequences on NMJ stability and the role of mitochondrial dysfunction, delving into their complex relationship with ageing and disuse. Evidence suggests that mitochondrial dysfunction can be a pathogenic driver for NMJ alterations, with studies revealing the role of mitochondrial defects in motor neuron degeneration and NMJ instability. Two perspectives behind NMJ instability are discussed: one is that mitochondrial dysfunction in skeletal muscle triggers NMJ deterioration, the other envisages dysfunction of motor terminal mitochondria as a primary contributor to NMJ instability. While evidence from these studies supports both perspectives on the relationship between NMJ dysfunction and mitochondrial impairment, gaps persist in the understanding of how mitochondrial dysfunction can cause NMJ deterioration. Further research, both in humans and in animal models, is essential for unravelling the mechanisms and potential interventions for age- and inactivity-related neuromuscular and mitochondrial alterations.

Aspartame intake during pregnancy induces placental dysfunction through impaired mitochondrial function and biogenesis modulation

Aspartame is a nonnutritive sweetener (NSS), which is widely used in foods and beverages worldwide. The safety of aspartame, a commonly used artificial sweetener, has been debated. Here, we investigated the potential effects and underlying mechanisms of aspartame consumption during pregnancy on placental dysfunction and birth outcomes. Female Sprague Dawley rats were exposed to a low (30mg/kg) or high (60mg/kg) dose of aspartame before and during pregnancy; moreover, we assessed placental histopathological structure, oxidative stress markers, and mitochondrial function. In addition, we explored how aspartame affects birth weight in a human maternal-infant cohort. In animal study revealed that aspartame treatment of female rats for 14 weeks (12 week before pregnancy and 18 days of gestation) causes a significant reduction in the number and weight of fetuses, as well as damage to placental structure. These effects are linked to increased oxidative stress in the placenta, possibly damaging placental trophoblasts, impairing mitochondrial function, and initiating a compensatory mitochondrial biosynthesis mechanism. In the human pregnant cohort revealed that aspartame reduces birth weight considerably. These findings suggested the potential risks associated with aspartame consumption during pregnancy. Therefore, the safety of aspartame, particularly in pregnant individuals, should be reconsidered; specifically, tailored, acceptable daily intake guidelines should be developed for aspartame in different populations.

Unravelling Neuroinflammation-Mediated Mitochondrial Dysfunction in Mild Cognitive Impairment: Insights from Targeted Metabolomics

BackgroundThe prevalence of Type 2 Diabetes Mellitus (T2DM) is rising rapidly among the elderly due to age-related metabolic changes. Older adults with T2DM have a 50-65% increased risk of developing cognitive impairment, particularly mild cognitive impairment (MCI), which may progress to neurodegenerative conditions like Alzheimer's disease (AD). Recent studies underscore the significant roles of mitochondrial dysfunction, disrupted glutamate-glutamine cycling, hyperglycemia, and hyperprolinemia in cognitive decline. These interconnected metabolites—glucose, glutamine, glutamate, and proline—are potential targets for understanding the relationship between T2DM and cognitive impairment. Material and MethodThe present targeted NMR based metabolomics study aims to compare the blood plasma/serum metabolic profiles of these four metabolites in age and sex matched MCI (N=27) and T2DM patients (N=38) with respect to normal control (NC, N=23) subjects. The metabolic profiling was performed using 1H NMR spectroscopy. ResultsCompared to NC group, both T2DM and MCI groups exhibited elevated glucose levels. Circulatory glucose and glutamine levels were significantly higher in T2DM subjects than in MCI and NC subjects, while glutamate levels followed a similar trend in both T2DM and MCI groups. However, in MCI patients, circulatory proline and proline-to-glutamine (PQR) and glutamate-to-glutamine was significantly elevated compared to T2DM, while glutamine was significantly reduced. ConclusionThe decreased circulatory levels of glutamine and PQR demonstrated statistically significant correlation with the severity of the cognitive impairment as assessed based on Mini Mental State Examination (MMSE) score suggested augmented utilization of glutamine in MCI patients and accumulation to proline due to active neuro-inflammatory processes and impaired mitochondrial functioning in MCI brain.

Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.

Pathogenic variants in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial function. Within this group, an increasing number of families have been identified, where Mendelian genetic disorders implicate defective mitochondrial RNA biology. The PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Here, we report that disease-causing PDE12 variants in three unrelated families are associated with mitochondrial respiratory chain deficiencies and wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. Whole exome sequencing of affected probands revealed novel, segregating bi-allelic missense PDE12 variants affecting conserved residues. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing (MPAT-Seq) revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein. Our data suggest that PDE12 regulates mitochondrial RNA processing and its loss results in neurological and muscular phenotypes.

Benefits of Astaxanthin supplementation: selected issues

INTRODUCTION: Astaxanthin, a carotenoid compound belonging to the xanthophyll group, occurs naturally in algae, yeast, and marine organisms such as shrimp, trout, lobster, and krill. Renowned for its antioxidant prowess, astaxanthin shields mitochondria from harm caused by reactive oxygen species (ROS). Its exceptional antioxidant potency is noteworthy, surpassing that of α-tocopherol (Vitamin E) by 100-fold and eclipsing over 600 other recognized natural carotenoids. REVIEW METHODS: The article was complied by analyzing data from PubMed and Google Scholar data regarding the benefits of astaxanthin supplementation. THE STATE OF KNOWLEDGE: Astaxanthin, offers a range of health benefits. It modulates immune responses, inhibits cancer cell growth, reduces bacterial presence and gastric inflammation. With potent antioxidant properties, it also serves as a neuroprotective agent by combating neuroinflammation. Additionally, astaxanthin shows promise in preventing and treating liver diseases, thanks to its antioxidant, anti-inflammatory, and signaling pathway regulation properties. Overall, antioxidants like astaxanthin, whether from diet or supplements, help combat lipid and protein oxidation, thereby slowing down the progression of atherosclerosis. CONCLUSION: Astaxanthin emerges as a promising candidate for treating various pathological conditions linked to oxidative damage and impaired mitochondria function. These conditions span across cardiovascular diseases, neurodegenerative disorders and liver diseases. It could also help healthy people like athletes in enhancement of overall quality of life.

Abstract 4114308: Defective in LYPLA1-Mediated Lysophosphatidylcholine Metabolism Contributes to Diabetes-Induced Atherosclerosis and Subsequent Myocardial Dysfunction

Background and Objective: Diabetes mellitus (DM) is a chronic metabolic condition that can cause serious damage to blood vessels and the heart. While current metabolomics research mainly focused on metabolic profiles during disease onset or at advanced stages, there remains a gap in understanding the molecular mechanisms of metabolites in the progression of diabetic cardiovascular disease. This study aims to explore effective strategies for preventing cardiovascular complications in diabetics by excavating metabolic pathways and mechanisms. Methods: Peripheral blood samples were obtained from 21 healthy individuals, 20 patients diagnosed with DM, 20 patients with coronary heart disease (CHD), and 25 patients with both DM and CHD (DC). Cardiac function, biochemical parameters and serum metabolome were detected. A specialized methodology with rigorous screening criteria was employed to identify differential metabolites associated with diabetes-induced CHD and cardiomyopathy. Mice were injected with LPC16:0 to assess cardiovascular function. Models of diabetes and diabetic atherosclerosis were induced by STZ injection and high-fat diet feeding in WT and ApoE -/- mice. Cardiac function and differential metabolites in aortic and cardiac tissues were assessed. The effect and molecular mechanism of LYPLA1 on vascular function, mitochondrial function, and metabolites-related enzymes were examined in human aortic endothelial cells (HAECs) and AC16 cardiomyocytes. Results: Cardiac function was markedly declined in DM and DC patients, as well as in mice with diabetes and diabetic atherosclerosis. However, CHD patients and atherosclerosis alone did not exhibit evident cardiac dysfunction. Key metabolites associated with diabetic cardiomyopathy and diabetes-induced CHD were identified as LPE18:1 and LPC16:0, respectively. Intraperitoneal administration of LPC16:0 in mice led to decreased LYPLA1, severe myocardial anomalies, and the appearance of plaques in the aortic arch. Either LYPLA1 knockdown or the treatment with high glucose and palmitic acid in HAECs resulted in impaired mitochondrial function, reduced intracellular NO and eNOS activity, which were mitigated by LYPLA1 overexpression. Conclusion: The metabolite LPC16:0 and the regulatory enzyme LYPLA1 are pivotal in driving the advancement of cardiovascular complications triggered by diabetes. Targeting LYPLA1 could represent a promising strategy for preventing diabetes-induced CHD and subsequent cardiomyopathy.

Abstract 4122257: Inhibition of Neutrophil Extracellular Traps Prevents Heart Failure by Preserving Mitochondrial Function of Cardiomyocytes in Mice

Background: We have previously demonstrated that neutrophil extracellular traps (NETs) in myocardial tissue are associated with cardiac dysfunction and adverse outcomes in patients with heart failure with reduced ejection fraction. Here, we aimed to elucidate the underlying mechanisms and to clarify whether inhibiting NETs could rescue the cardiac phenotype using ex vivo and in vivo models. Methods and Results: Given that peptidyl arginine deiminase 4 (PAD4) is essential for the formation of NETs, PAD4 knockout mice were used for this study. First, we assessed the mitochondrial function of cardiomyocytes by conducting real-time measurements of the oxygen consumption rate in ex vivo . Extracellular flux analysis revealed that NETs-containing conditioned medium from wild-type neutrophils or purified NET components led to impaired mitochondrial oxygen consumption of adult mouse cardiomyocytes, while these effects were abolished when PAD4 in neutrophils was genetically ablated (Figure 1). In a murine model of pressure overload-induced heart failure, transverse aortic constriction (TAC) operation was performed on wild-type and PAD4 knockout mice. Immunohistological analysis demonstrated that TAC induced the formation of NETs in the myocardium, with the greatest number of NETs occurring at 1 day, persisting into the failing stage at 4 weeks in wild-type mice, while PAD4-deficient hearts displayed no presence of NETs in the heart tissue (Figure 2). Four weeks after TAC, left ventricular ejection fraction was reduced in wild-type mice, whereas PAD4 knockout mice displayed preserved left ventricular ejection fraction (Figure 2). Finally, we investigated the bioenergetics of cardiomyocytes isolated from PAD4 knockout mice after TAC. Maximal mitochondrial oxygen consumption rate in cardiomyocytes isolated from TAC-operated PAD4 knockout mice was significantly higher than in those from TAC-operated wild-type mice (Figure 3). Conclusion: Our data suggest that NETs directly derived impairment of mitochondrial function in cardiomyocytes. Inhibiting NETs represents a potential therapeutic approach for heart failure, preventing mitochondrial dysfunction of cardiomyocytes.

40 Hz light preserves synaptic plasticity and mitochondrial function in Alzheimer’s disease model

Alzheimer’s disease (AD) is the most prevalent type of dementia. Its causes are not fully understood, but it is now known that factors like mitochondrial dysfunction, oxidative stress, and compromised ion channels contribute to its onset and progression. Flickering light therapy has shown promise in AD treatment, though its mechanisms remain unclear. In this study, we used a rat model of streptozotocin (STZ)-induced AD to evaluate the effects of 40 Hz flickering light therapy. Rats received intracerebroventricular (ICV) STZ injections, and 7 days after, they were exposed to 40 Hz flickering light for 15 min daily over seven days. Cognitive and memory functions were assessed using Morris water maze, novel object recognition, and passive avoidance tests. STZ-induced AD rats exhibited cognitive decline, elevated reactive oxygen species, amyloid beta accumulation, decreased serotonin and dopamine levels, and impaired mitochondrial function. However, light therapy prevented these effects, preserving cognitive function and synaptic plasticity. Additionally, flickering light restored mitochondrial metabolites and normalized ATP-insensitive mitochondrial calcium-sensitive potassium (mitoBKCa) channel activity, which was otherwise downregulated in AD rats. Our findings suggest that 40 Hz flickering light therapy could be a promising treatment for neurodegenerative disorders like AD by preserving synaptic and mitochondrial function.

Exploring the role of Cdk5 on striatal synaptic plasticity in a 3-NP-induced model of early stages of Huntington's disease.

Impaired mitochondrial function has been associated with the onset of neurodegenerative diseases. Specifically, certain mitochondrial toxins, such as 3-nitropropionic acid (3-NP), initiate cellular changes within the striatum that closely resemble the pathology observed in Huntington's disease (HD). Among the pivotal signaling molecules contributing to neurodegeneration, cyclin-dependent kinase 5 (Cdk5) stands out. In particular, Cdk5 has been implicated not only in cellular pathology but also in the modulation of synaptic plasticity. Given its widespread presence in the striatum, this study seeks to elucidate the potential role of Cdk5 in the induction of corticostriatal synaptic plasticity in murine striatal cells subjected to subchronic doses of 3-NP in vivo, aiming to mimic the early stages of HD. Immunostaining analyses revealed an increase in Cdk5 in tissues from animals treated with 3-NP, without a significant change in protein levels. Regarding striatal plasticity, long-term depression (LTD) was induced in both control and 3-NP cells when recorded in voltage clamp mode. The Cdk5 inhibitor roscovitine-reduced LTD in most cells. A minority subset of cells exhibited long-term potentiation (LTP) generation in the presence of roscovitine. The inhibitor of D1 receptors SCH23390 prevented LTP in three of nine cells, implying that MSN cells lacking D1/PKA activation were capable of LTP induction when Cdk5 was also blocked. Nevertheless, the co-administration of H89, a PKA inhibitor, along with roscovitine, prevented the generation of any type of plasticity in all recorded cells. These findings show the impact of 3-NP treatment on striatal plasticity and suggest that Cdk5 during early neurodegeneration may attenuate signaling pathways that lead neurons to increase their activity.

The interplay of oxidative stress, apoptotic signaling, and impaired mitochondrial function in the pyrethroid-induced cardiac injury: Alleviative role of curcumin-loaded chitosan nanoparticle

This study assessed the consequence of exposure to a pyrethroid insecticide, fenpropathrin (FPN), on the heart and the probable underlying mechanisms in rats. Moreover, the probable protective effect of curcumin-loaded chitosan nanoparticles (CMN-CNP) was evaluated. Forty male Sprague Dawley rats were distributed into four groups orally given corn oil, CMN-CNP (50 mg/kg b.wt), FPN (15 mg/kg b.wt), or CMN-CNP + FPN for 60 days. The results revealed that FPN exposure increased serum cardiac damage indicators. In addition, a substantial increase in the reactive oxygen species and malondialdehyde content but reduced enzymatic and non-enzymatic antioxidants and altered architecture was recorded in the cardiac tissue of FPN-exposed rats. Additionally, a significant down-regulation of expression of the mitochondrial complexes I–V, mitochondrial dynamics, and antioxidants-related genes but up-regulation of apoptosis-related genes was detected in the FPN-exposed group. Immunofluorescence analyses revealed higher amounts of the harmful protein 4-hydroxynonenal in the heart tissue of FPN-exposed rats. Nevertheless, the earlier disturbances were significantly rescued in the FPN + CMN-CNP treated group. Conclusively, our findings reported the cardiotoxic activity of FPN and the involvement of several mitochondrial imbalances as a probable underlying mechanism. Also, the study findings proved the efficacy of CMN-CNP in combating FPN cardiotoxic effects.

Diabetic Cardiomyopathy: An Update on Emerging Pathological Mechanisms.

Diabetic Cardiomyopathy (DCM) is a notable consequence of diabetes mellitus, distinguished by cardiac dysfunction that occurs separately from coronary artery disease or hypertension. A recent study has revealed an intricate interaction of pathogenic processes that contribute to DCM. Important aspects involve the dysregulation of glucose metabolism, resulting in heightened oxidative stress and impaired mitochondrial function. In addition, persistent high blood sugar levels stimulate inflammatory pathways, which contribute to the development of heart fibrosis and remodelling. Additionally, changes in the way calcium is managed and the presence of insulin resistance are crucial factors in the formation and advancement of DCM. This may be due to the involvement of many molecular mechanistic pathways such as NLRP3, NF- κB, PKC, and MAPK with their downstream associated signaling pathways. Gaining a comprehensive understanding of these newly identified pathogenic pathways is crucial in order to design precise therapy approaches that can enhance the results for individuals suffering from diabetes. In addition, this review offers an in-depth review of not just pathogenic pathways and molecular mechanistic pathways but also diagnostic methods, treatment options, and clinical trials.

F2,6BP restores mitochondrial genome integrity in Huntington's Disease.

Several reports have indicated that impaired mitochondrial function contributes to the development and progression of Huntington's disease (HD). Mitochondrial genome damage, particularly DNA strand breaks (SBs), is a potential cause for its compromised functionality. We have recently demonstrated that the activity of polynucleotide kinase 3'-phosphatase (PNKP), a critical DNA end-processing enzyme, is significantly reduced in the nuclear extract of HD patients due to lower level of a metabolite fructose-2,6 bisphosphate (F2,6BP), a biosynthetic product of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3), leading to persistent DNA SBs with 3'-phosphate termini, refractory to subsequent steps for repair completion. PNKP also plays a pivotal role in maintaining mitochondrial genome integrity. In this report, we provide evidence that both PFKFB3 and F2,6BP, an allosteric modulator of glycolysis, are also present in the mitochondria. Notably, the level of F2,6BP, a cofactor of PNKP, is significantly decreased due to the degradation of PFKFB3 in the mitochondrial extract of HD patients' brain. PNKP activity is thus severely decreased in the mitochondrial extract; however, addition of F2,6BP restored PNKP activity. Moreover, supplementation of F2,6BP in HD mouse striatal neuronal cells restored mitochondrial genome integrity and partially restored mitochondrial membrane potential and prevented pathogenic aggregate formation. We observed similar restoration of mitochondrial genome integrity in HD drosophila supplemented with F2,6BP. Our findings, therefore, suggest that F2,6BP or its structural analog hold promise as a therapeutic for restoring both nuclear and mitochondrial genome integrity and thereby of organismal health.

Air pollutants as modulators of mitochondrial quality control in cardiovascular disease.

It is important to understand the effects of environmental factors such as air pollution on mitochondrial structure and function, especially when these changes increase cardiovascular disease risk. Although lifestyle choices directly determine many mitochondrial diseases, increasingly, it is becoming clear that the structure and function of mitochondria may be affected by pollutants found in the atmosphere (e.g., gases, pesticides herbicide aerosols, or microparticles). To date, the role of such agents on mitochondria and the potential impact on cardiovascular fitness is neglected. Here we offer a review of airborne stressors and pollutants, that may contribute to impairments in mitochondrial function and structure to cause heart disease.

Lactate supplementation after hypoglycemia alleviates cognitive dysfunction induced by recurrent non-severe hypoglycemia in diabetic mice

Recurrent non-severe hypoglycemia (RH) in diabetes is an independent risk factor for cognitive dysfunction. However, the mechanisms and potential therapeutic strategies remain poorly understood. In this study, we aimed to elucidate the mechanisms underlying RH-induced diabetic cognitive impairment. We investigated the effects of RH on lactate metabolism and cognitive function in male C57BL/6 J diabetic mice. After RH, diabetic mice showed decreased brain lactate and adenosine triphosphate levels, decreased expression of lactate transporter proteins MCT1 and MCT4, increased neuroapoptosis, and decreased astrocyte glycolysis in vitro. This was accompanied by increased neuronal mitochondrial reactive oxygen species levels, decreased mitochondrial COX IV activity, impaired mitochondrial morphology and function, impaired synaptic morphology, and decreased expression of synaptic plasticity proteins. Intraperitoneal lactic acid injection improved lactate transport restored neuronal mitochondrial morphology and function, upregulated synaptic plasticity proteins brain-derived neurotrophic factor and early growth response 1, enhanced synaptic ultrastructure, and ultimately improved cognitive dysfunction following RH in diabetic mice. These findings provide insights into the prevention and treatment of cognitive dysfunction in patients with diabetes mellitus caused by RH.

Effect of exogenous ketone supplementation on cardiac energetics, function, and perfusion in type 2 diabetes, heart failure, and healthy participants- A single center, open labelled clinical study

Abstract Background Type 2 diabetes (T2D) confers loss of cardiac metabolic flexibility in fuel selection and impaired mitochondrial function. Enhanced ketone metabolism observed in T2D may represent a compensatory adaptive mechanism as ketones are a more energy efficient resource than carbohydrates or fatty acids. Favorable energetic properties of ketones may potentially mitigate the energy starved state in T2D and heart failure (HF). Purpose To test whether exogenous oral ketone supplementation would reverse cardiac energetic deficit, as well as improve cardiac function and perfusion in patients with T2D, with HF with reduced ejection fraction (HFrEF), and healthy volunteers (HV). Methods Three groups of patients were recruited: patients with T2D (n=33); patients with HFrEF (n=29, 14 with T2D); and HVs(n=25). Participants underwent cardiovascular magnetic resonance and spectroscopy to assess left ventricular (LV) function, rest and dobutamine stress perfusion and energetics (phosphocreatine/adenosine triphosphate ratio[PCr/ATP]). After the initial visit, participants had an identical second visit following 2 weeks of oral ketone supplementation (30g daily). Results Participants were matched in age and sex distribution. There were no significant differences in LV ejection fraction (LVEF) between T2D and HV groups with significantly lower LVEF in HFrEF group. Both the T2D group and the HFrEF group showed significant reductions in PCr/ATP ratio and the rest and stress GLS compared to the HV. The resting and dobutamine-stress myocardial blood flow (MBF) were only significantly reduced in patients with HFrEF compared to T2D and HV groups. Subgroup analyses of HFrEF group with and without T2D showed no significant differences in energetics, perfusion, or functional assessments. Significant increase in PCr/ATP ratio was seen only in T2D group from baseline after 2 weeks of ketone supplementation (Visit-1:1.6[1.5,1.8] vs Visit-2:1.9[1.7,2.1]; P=0.01). This significant increment was not observed in HFrEF or HV groups. Two weeks of ketone supplementation was not associated with any significant changes in LVEF, GLS, rest or dobutamine-stress myocardial blood flow, or in myocardial lipid content (Table-1). Conclusions Short-term ketone supplementation is associated with isolated significant improvements in resting cardiac energetics in patients with T2D and preserved LVEF, without changes cardiac function or perfusion. In contrast to patients with T2D and preserved LVEF, short-term ketone supplementation does not lead to any significant improvements in energetics in patients with HFrEF suggesting loss of mitochondrial plasticity with transition to HFrEF. Moreover, healthy volunteers experience no further increments of myocardial energetics from the normal range values at baseline with ketone supplementation.