Search results
Found 12696 matches for
Mitochondrial calcium uptake
Calcium (Ca 2+ ) uptake into the mitochondrial matrix is critically important to cellular function. As a regulator of matrix Ca 2+ levels, this flux influences energy production and can initiate cell death. If large, this flux could potentially alter intracellular Ca 2+ ([Ca 2+ ] i ) signals. Despite years of study, fundamental disagreements on the extent and speed of mitochondrial Ca 2+ uptake still exist. Here, we review and quantitatively analyze mitochondrial Ca 2+ uptake fluxes from different tissues and interpret the results with respect to the recently proposed mitochondrial Ca 2+ uniporter (MCU) candidate. This quantitative analysis yields four clear results: ( i ) under physiological conditions, Ca 2+ influx into the mitochondria via the MCU is small relative to other cytosolic Ca 2+ extrusion pathways; ( ii ) single MCU conductance is ∼6–7 pS (105 mM [Ca 2+ ]), and MCU flux appears to be modulated by [Ca 2+ ] i , suggesting Ca 2+ regulation of MCU open probability ( P O ); ( iii ) in the heart, two features are clear: the number of MCU channels per mitochondrion can be calculated, and MCU probability is low under normal conditions; and ( iv ) in skeletal muscle and liver cells, uptake per mitochondrion varies in magnitude but total uptake per cell still appears to be modest. Based on our analysis of available quantitative data, we conclude that although Ca 2+ critically regulates mitochondrial function, the mitochondria do not act as a significant dynamic buffer of cytosolic Ca 2+ under physiological conditions. Nevertheless, with prolonged (superphysiological) elevations of [Ca 2+ ] i , mitochondrial Ca 2+ uptake can increase 10- to 1,000-fold and begin to shape [Ca 2+ ] i dynamics.
Clinical indications and patient outcomes of intracranial venous sinus stenting beyond overt idiopathic intracranial hypertension: a scoping review.
BACKGROUND: Intracranial venous sinus stenting (VSS) was initially developed as an alternative approach to addressing venous outflow obstruction in the context of idiopathic intracranial hypertension (IIH). In recent years, the technique has been increasingly used for other conditions involving venous compromise beyond overt IIH. The aim of this study was to describe the nature and volume of literature considering clinical applications and efficacy of VSS. METHODS: A scoping review was conducted using MEDLINE, EMBASE, Scopus, The Cochrane Library, and various grey literature sources. Articles published since the introduction of VSS in 2002 were included. Independent screening of articles occurred in two stages: title-and-abstract and full-text screening. Relevant data was extracted and evidence mapping with narrative synthesis followed. RESULTS: The search strategy yielded 1814 articles, of which 165 were included in this review. A total of 27 additional clinical indications of VSS beyond overt IIH were identified, spanning a diverse range of neurological pathology. Most evidence came from case reports, with the United States being the commonest study origin. Focal stenotic lesions and stenting locations were distributed throughout the dural sinus anatomy. An outline of patient outcomes reported by VSS providers is presented, with pulsatile tinnitus and visual impairment showing the greatest likelihood of clinical resolution. CONCLUSION: This scoping review demonstrates the wider clinical utility and therapeutic potential of VSS beyond overt IIH. We also highlight the need for further studies to assess efficacy for each respective indication and clinical standardisation of VSS practice.
Y12C mutation disrupts IMPDH cytoophidia and alters cancer metabolism.
Guanosine triphosphate (GTP) is a building block for DNA and RNA, and plays a pivotal role in various cellular functions, serving as an energy source, enzyme cofactor and a key component of signal transduction. The activity of the rate-limiting enzyme in de novo GTP synthesis, inosine monophosphate dehydrogenase (IMPDH), is regulated by nucleotide binding. Recent studies have illuminated that IMPDH octamers can assemble into linear polymers, adding another dimension to its enzymatic regulation. This polymerisation reduces IMPDH's sensitivity to the inhibitory effects of GTP binding, thereby augmenting its activity under conditions with elevated GTP levels. Within cells, IMPDH polymers may cluster to form the distinctive structure known as the cytoophidium, which is postulated to reflect the cellular demand for increased GTP concentrations. Nevertheless, the functional significance of IMPDH polymerisation in in vivo metabolic regulation remains unclear. In this study, we report the widespread presence of IMPDH cytoophidia in various human cancer tissues. Utilising the ABEmax base editor, we introduced a Y12C point mutation into IMPDH2 across multiple cancer cell lines. This mutation disrupts the polymerisation interface of IMPDH and prevents cytoophidium assembly. In some cancer xenografts, the absence of IMPDH polymers led to a downregulation of IMPDH, as well as the glycolytic and pentose phosphate pathways. Furthermore, mutant HeLa-cell-derived xenografts were notably smaller than their wild-type counterparts. Our data suggest that IMPDH polymerisation and cytoophidium assembly could be instrumental in modulating metabolic homeostasis in certain cancers, offering insights into the clinical relevance of IMPDH cytoophidium.
Cognitive and neuropsychiatric profiles distinguish atypical parkinsonian syndromes.
Atypical parkinsonian syndromes are distinguished from Parkinson's disease by additional neurological signs and characteristic underlying neuropathology. However, they can be diagnostically challenging, rapidly progressive, and are often diagnosed late in disease course. Their different demographic features and prognoses are well studied, but the accompanying cognitive and psychiatric features may also facilitate diagnosis. Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) may cause cognitive and behavioural manifestations that overlap with frontotemporal dementia, including non-fluent aphasia, apathy and impulsivity. Clinical diagnostic criteria have limited sensitivity, with pathologically confirmed PSP often having presented an initial clinical syndrome other than PSP-Richardson's syndrome. Here we integrate cross-sectional multi-centre baseline data from the PROSPECT and Oxford Discovery cohorts. This allowed us to compare cognitive and psychiatric features across a total of 1138 people with PSP, CBS, multiple-system atrophy (MSA), and idiopathic Parkinson's disease (PD). Data from the different cohorts were harmonised and compared using multiple linear regression. There were five key results. 1. Different syndromes showed distinctive cognitive profiles, using readily applicable 'bedside' screening tools. Frontal executive dysfunction was most evident in PSP, visuospatial deficits in CBS, with milder deficits in memory and executive function in MSA, as compared with PD. 2. The most prevalent neuropsychiatric features were depression and anxiety in CBS, apathy in PSP, with sleep disturbances common in PD. As expected, apathy correlated positively with impulsivity across all disorders. Neuropsychiatric features were generally better at discriminating between atypical parkinsonian syndromes than were the cognitive domains. 3. Both cognitive function and motor severity declined with disease duration, and motor function predicted cognition in PSP, CBS and PD but not in MSA, suggesting that in MSA cognitive and motor dysfunction are decoupled. 4. Plasma neurofilament light chain (NFL) levels, measured in a subset of patients, correlated with cognitive deficits in PSP, but not motor deficits. 5. Cognitive deficits contributed to the impairment in activities of daily living after controlling for motor severity, with every two points on the MoCA worsening the Schwab and England score by one point. In anticipation of future neuroprotective therapies, we present a classifier to improve diagnostic accuracy for atypical parkinsonian syndromes in vivo. Longitudinal cohort studies with resources for neuropathological gold-standard diagnosis remain important to validate better diagnostic tools for people with PSP, CBD, MSA and atypical parkinsonism.
Hyperpolarized 13C-MRS can Quantify Lactate Production and Oxidative PDH Flux in Murine Skeletal Muscle During Exercise.
Existing techniques for the non-invasive in vivo study of dynamic changes in skeletal muscle metabolism are subject to several limitations, for example, poor signal-to-noise ratios which result in long scan times and low temporal resolution. Hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy (HP-MRS) allows the real-time visualization of in vivo metabolic processes and has been used extensively to study cardiac metabolism, but has not resolved oxidative phosphorylation in contracting skeletal muscle. Combining HP-MRS with an in vivo muscle hindlimb electrical stimulation protocol that modelled voluntary exercise to exhaustion allows the simultaneous real-time assessment of both metabolism and function. The aim of this work was to validate the sensitivity of the method by assessing pyruvate dehydrogenase (PDH) flux in resting vs. working muscle: measuring the production of bicarbonate (H13CO3 -), a byproduct of the PDH-catalysed conversion of [1-13C]pyruvate to acetyl-CoA. Mice (n = 6) underwent two hyperpolarized [1-13C]pyruvate injections with 13C MR spectra obtained from the gastrocnemius muscle to measure conversion of pyruvate to lactate and bicarbonate, one before the stimulation protocol with the muscle in a resting state and one during the stimulation protocol. The muscle force generated during stimulation was also measured, and 13C MRS undertaken at a point of ~50% fatigue. We observed an increase in the bicarbonate/pyruvate ratio by a factor of ~1.5×, in the lactate/pyruvate ratio of ~2.7×, together with an increase in total carbon (~1.5×) that we attribute to perfusion. This demonstrates profound differences in metabolism between the resting and exercising states. These data therefore serve as preliminary evidence that hyperpolarized 13C MRS is an effective in vivo probe of PDH flux in exercising skeletal muscle and could be used in future studies to examine changes in muscle metabolism in states of disease and altered nutrition.
The transcription factor Traffic jam orchestrates the somatic piRNA pathway in Drosophila ovaries
The PIWI-interacting RNA (piRNA) pathway is essential for transposable element (TE) silencing in animal gonads. While the transcriptional regulation of piRNA pathway components in germ cells has been documented in mice and flies, their control in somatic cells of Drosophila ovaries remains unresolved. Here, we demonstrate that Traffic jam (Tj), the Drosophila ortholog of large Maf transcription factors in mammals, is a master regulator of the somatic piRNA pathway. Tj binds to regulatory regions of somatic piRNA factors and the major piRNA cluster flamenco, which carries a Tj-bound enhancer downstream of its promoter. Depletion of Tj in somatic follicle cells causes downregulation of piRNA factors, loss of flamenco expression, and derepression of gypsy-family TEs. We propose that the arms race between the host and TEs led to the co-evolution of promoters in piRNA pathway genes as well as TE regulatory regions, which both rely on a shared transcription factor.