Thiamine (vitamin B1) is an essential nutrient that serves as a cofactor for a number of enzymes, mostly with mitochondrial localization. Some thiamine-dependent enzymes are involved in energy ...metabolism and biosynthesis of nucleic acids whereas others are part of the antioxidant machinery. The brain is highly vulnerable to thiamine deficiency due to its heavy reliance on mitochondrial ATP production. This is more evident during rapid growth (i.e., perinatal periods and children) in which thiamine deficiency is commonly associated with either malnutrition or genetic defects. Thiamine deficiency contributes to a number of conditions spanning from mild neurological and psychiatric symptoms (confusion, reduced memory, and sleep disturbances) to severe encephalopathy, ataxia, congestive heart failure, muscle atrophy, and even death. This review discusses the current knowledge on thiamine deficiency and associated morbidity of neurological and psychiatric disorders, with special emphasis on the pediatric population, as well as the putative beneficial effect of thiamine supplementation in autism spectrum disorder (ASD) and other neurological conditions.
The effects of nitric oxide in biological systems depend on its steady-state concentration and where it is being produced. The organ where nitric oxide is produced is relevant, and within the organ, ...which types of cells are actually contributing to this production seem to play a major determinant of its effect. Subcellular compartmentalization of specific nitric oxide synthase enzymes has been shown to play a major role in health and disease. Pathophysiological conditions affect the cellular expression and localization of nitric oxide synthases, which in turn alter organ cross talk. In this study, we describe the compartmentalization of nitric oxide in organs, cells, and subcellular organelles and how its localization relates to several relevant clinical conditions. Understanding the complexity of the compartmentalization of nitric oxide production and the implications of this compartmentalization in terms of cellular targets and downstream effects will eventually contribute toward the development of better strategies for treating or preventing pathological events associated with the increase, inhibition, or mislocalization of nitric oxide production.
No proven prognosis is available for the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Artificial neural network analyses (ANN) were used to predict FXTAS ...progression using data from 127 adults (noncarriers and FMR1 premutation carriers with and without FXTAS) with five outcomes from brain MRI imaging and 22 peripheral bioenergetic outcomes from two cell types. Diagnosis accuracy by ANN predictions ranged from 41.7 to 86.3% (depending on the algorithm used), and those misclassified usually presented a higher FXTAS stage. ANN prediction of FXTAS stages was based on a combination of two imaging findings (white matter hyperintensity and whole-brain volumes adjusted for intracranial volume) and four bioenergetic outcomes. Those at Stage 3 vs. 0-2 showed lower mitochondrial mass, higher oxidative stress, and an altered electron transfer consistent with mitochondrial unfolded protein response activation. Those at Stages 4-5 vs. 3 had higher oxidative stress and glycerol-3-phosphate-linked ATP production, suggesting that targeting mGPDH activity may prevent a worse prognosis. This was confirmed by the bioenergetic improvement of inhibiting mGPDH with metformin in affected fibroblasts. ANN supports the prospect of an unbiased molecular definition in diagnosing FXTAS stages while identifying potential targets for personalized medicine.
CGG expansions between 55 and 200 in the 5′-untranslated region of the fragile-X mental retardation gene (FMR1) increase the risk of developing the late-onset debilitating neuromuscular disease ...Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). While the science behind this mutation, as a paradigm for RNA-mediated nucleotide triplet repeat expansion diseases, has progressed rapidly, no treatment has proven effective at delaying the onset or decreasing morbidity, especially at later stages of the disease. Here, we demonstrated the beneficial effect of the phytochemical sulforaphane (SFN), exerted through NRF2-dependent and independent manner, on pathways relevant to brain function, bioenergetics, unfolded protein response, proteosome, antioxidant defenses, and iron metabolism in fibroblasts from FXTAS-affected subjects at all disease stages. This study paves the way for future clinical studies with SFN in the treatment of FXTAS, substantiated by the established use of this agent in clinical trials of diseases with NRF2 dysregulation and in which age is the leading risk factor.
•Sulforaphane improved mitochondrial bioenergetics in FXTAS.•Bioenergetic improvement was observed with high CGG repeats and disease stage.•Sulforaphane promoted NRF2-dependent and -independent mechanisms of action.
Targeted nitric oxide production is relevant for maintaining cellular energy production, protecting against oxidative stress, regulating cell death, and promoting neuroprotection. This study aimed to ...characterize the putative interaction of nitric-oxide synthase with mitochondrial proteins. The primary finding of this study is that cytochrome
oxidase (CCO) subunit IV (CCOIV) is associated directly with NOS in brain mitochondria when calcium ions are present. The matrix side of CCOIV binds to the
-terminus of NOS, supported by the abrogation of the binding by antibodies towards the
-terminus of NOS. Evidence supporting the interaction between CCOIV and NOS was provided by the coimmunoprecipitation of NOS from detergent-solubilized whole rat brain mitochondria with antibodies to CCOIV and the coimmunoprecipitation of CCOIV from crude brain NOS preparations using antibodies to NOS. The CCOIV domain that interacts with NOS was identified using a series of overlapping peptides derived from the primary sequence of CCOIV. As calcium ions not only activate NOS, but also facilitate the docking of NOS to CCOIV, this study points to a dynamic mechanism of controlling the bioenergetics by calcium changes, thereby adapting bioenergetics to cellular demands.
Polybrominated diphenyl ethers (PBDEs) represent an important group of flame retardants extensively used, tonnage of which in the environment has been steadily increasing over the past 25 years. ...PBDEs or metabolites can induce neurotoxicity and mitochondrial dysfunction (MD) through a variety of mechanisms. Recently, PBDEs with < 5 Br substitutions (i.e., 2,2',4,4'-tetrabromodiphenyl ether BDE-47 and 2,2',4,5'-tetrabromodiphenyl ether BDE-49) have gained interest because of their high bioaccumulation. In particular, congeners such as BDE-49 arise as one of the most biologically active, with concentrations typically lower than those observed for BDE-47 in biological tissues; however, its potential to cause MD at biologically relevant concentrations is unknown. To this end, the effect of BDE-49 was studied in brain mitochondria and neuronal progenitor striatal cells (NPC). BDE-49 uncoupled mitochondria at concentrations < 0.1 nM, whereas at > 1 nM, it inhibited the electron transport at Complex V (mixed type inhibition; IC(50) = 6 nM) and Complex IV (noncompetitive inhibition; IC(50) = 40 nM). These concentrations are easily achieved in plasma concentrations considering that BDE-49 (this study, 400-fold) and other PBDEs accumulate 1-3 orders of magnitude in the cells, particularly in mitochondria and microsomes. Similar effects were observed in NPC and exacerbated with PTEN (negative modulator of the PI3K/Akt pathway) deficiency, background associated with autism-like behavior, schizophrenia, and epilepsy. PBDE-mediated MD per se or enhanced by a background that confers susceptibility to this exposure may have profound implications in the energy balance of brain.
Limited studies are available on vitamin B6 status in domestic cats. To this end, we evaluated glutamate-oxaloacetate transaminase (GOT) activity in hemolysates with and without pyridoxal ...5'-phosphate addition in two feline populations: a cohort of 60 healthy, domestic (sexually intact and specific pathogen-free) cats maintained under strictly controlled conditions with appropriate diets housed at the Feline Nutrition and Pet Care Center, and a cohort of 57 cats randomly selected between December 2022 to January 2023 that visited the Veterinary Medicine Teaching Hospital to seek care under different circumstances. The GOT activity expressed as the ratio with and without pyridoxal 5'-phosphate addition (primary activation ratio; PAR) decreased significantly with age in the healthy cohort. The PAR values normalized to age established a cut-off for vitamin B6 deficiency in both cohorts, identifying 17 of 101 animals as vitamin B6 deficient. Using machine learning, a partition-based model (decision tree) was built to identify the most important factors that predicted vitamin B6 deficiency while using the resulting tree to make predictions for new observations. This analysis, performed with all 101 cats, revealed that the diagnosis of an infectious, chronic or acute condition (0.55) was the main contributor, followed by age (0.26), and body condition score (optimal-overweight; 0.19). Thus, our study supports that vitamin B6 supplementation may be indicated in junior to adult animals diagnosed with an infectious, chronic, or acute conditions or healthy cats with body weight ranging from optimal to overweight. In older cats, even if healthy, underweight to optimal cats appear to be at risk of vitamin B6 deficiency.
Changes in mitochondrial dynamics are often associated with dietary patterns, medical treatments, xenobiotics, and diseases. Toxic exposures to hydrogen sulfide (H2S) harm mitochondria by inhibiting ...Complex IV and via other mechanisms. However, changes in mitochondrial dynamics, including morphology following acute exposure to H2S, are not yet fully understood. This study followed mitochondrial morphology changes over time after a single acute LCt50 dose of H2S by examining electron microscopy thalami images of surviving mice. Our findings revealed that within the initial 48 h after H2S exposure, mitochondrial morphology was impaired by H2S, supported by the disruption and scarcity of the cristae, which are required to enhance the surface area for ATP production. At the 72-h mark point, a spectrum of morphological cellular changes was observed, and the disordered mitochondrial network, accompanied by the probable disruption of mitophagy, was tied to changes in mitochondrial shape. In summary, this study sheds light on how acute exposure to high levels of H2S triggers alterations in mitochondrial shape and structure as early as 24 h that become more evident at 72 h post-exposure. These findings underscore the impact of H2S on mitochondrial function and overall cellular health.
A 55-200 expansion of the CGG nucleotide repeat in the 5'-UTR of the fragile X mental retardation 1 gene (
) is the hallmark of the triplet nucleotide disease known as the "premutation" as opposed to ...those with >200 repeats, known as the full mutation or fragile X syndrome. Originally, premutation carriers were thought to be free of phenotypic traits; however, some are diagnosed with emotional and neurocognitive issues and, later in life, with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Considering that mitochondrial dysfunction has been observed in fibroblasts and post-mortem brain samples from carriers of the premutation, we hypothesized that mitochondrial dysfunction-derived ROS may result in cumulative oxidative-nitrative damage. Fibroblasts from premutation carriers (
=31, all FXTAS-free except 8), compared to age- and sex-matched controls (
=25), showed increased mitochondrial ROS production, impaired Complex I activity, lower expression of MIA40 (rate-limiting step of the redox-regulated mitochondrial-disulfide-relay-system), increased mtDNA deletions, and increased biomarkers of lipid and protein oxidative-nitrative damage. Most of the outcomes were more pronounced in FXTAS-affected individuals. Significant recovery of mitochondrial mass and/or function was obtained with superoxide or hydroxyl radicals' scavengers, a glutathione peroxidase analog, or by overexpressing MIA40. The effects of ethanol (a hydroxyl radical scavenger) were deleterious, while others (by
-acetyl-cysteine, quercetin and epigallocatechin-3-gallate) were outcome- and/or carrier-specifics. The use of antioxidants in the context of precision medicine is discussed with the goal of improving mitochondrial function in carriers with the potential of decreasing the morbidity and/or delaying FXTAS onset.
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