bims-medebr 2025-02-09 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–02–09
twenty papers selected by
Regina F. Fernández, Johns Hopkins University

Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD.
Quantitative assessment of brain metabolism in mice using non-contrast MRI at 11.7T.
Transcript and Lipid Profile Alterations in Astrocyte-Neuron Mitochondrial Transfer Under Lipopolysaccharide Exposure: An In Vitro Study.
Glutamate/GABA/glutamine ratios in intact and ischemia reperfusion challenged rat brain subregions, the effect of ischemic preconditioning.
Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
Lipid mediators in post-mortem brain samples from patients with Alzheimer's disease: A systematic review.
Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice.
Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
Mitochondrial dysfunction, iron accumulation, lipid peroxidation, and inflammasome activation in cellular models derived from patients with multiple sclerosis.
A mathematical model of microglia glucose metabolism and lactylation with positive feedback.
Practical experience and challenges in nutritional management of glucose transporter 1 deficiency syndrome: Provider survey results.
Novel intronic variant in NDUFS7 gene results in mitochondrial complex I assembly defect with early basal ganglia and midbrain involvement with progressive neuroimaging findings.
Prenatal protein deficiency causes age-specific alteration in number and distribution of inhibitory neurons in the somatosensory cortex during early postnatal development.
Lipid Biochemistry and its Role in Human Diseases.
The 1-acylglycerol-3-phosphate acyltransferase Slc1 is required to regulate mitochondria and lipid droplets.
Charcot Marie Tooth disease pathology is associated with mitochondrial dysfunction and lower glutathione production.
Applications of Metabolomics and Lipidomics in the Neonatal Intensive Care Unit.
MCU expression in hippocampal CA2 neurons modulates dendritic mitochondrial morphology and synaptic plasticity.
Rhodoquinone carries electrons in the mammalian electron transport chain.
Coupling between membrane undulations and lipid curvature leads to transient local enrichment of cardiolipin in mitochondrial membranes.

Mol Neurodegener. 2025 Feb 04. 20(1): 15

Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD.

Shaowei Wang, Boyang Li, Jie Li, Zhiheng Cai, Cristelle Hugo, Yi Sun, Lu Qian, Julia Tcw, Helena C Chui, Dante Dikeman, Isaac Asante, Stan G Louie, David A Bennett, Zoe Arvanitakis, Alan T Remaley, Bilal E Kerman, Hussein N Yassine.

   BACKGROUND: Cellular senescence, a hallmark of aging, has been implicated in Alzheimer's disease (AD) pathogenesis. Cholesterol accumulation is known to drive cellular senescence; however, its underlying mechanisms are not fully understood. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis, and its expression and trafficking are altered in APOE4 and AD models. However, the role of ABCA1 trafficking in cellular senescence associated with APOE4 and AD remains unclear.
METHODS: We examined the association between cellular senescence and ABCA1 expression in human postmortem brain samples using transcriptomic, histological, and biochemical analyses. Unbiased proteomic screening was performed to identify the proteins that mediate cellular ABCA1 trafficking. We created ABCA1 knock out cell lines and mouse models to validate the role of ABCA1 in cholesterol-induced mTORC1 activation and senescence. Additionally, we used APOE4-TR mice and induced pluripotent stem cell (iPSC) models to explore cholesterol-ABCA1-senescence pathways.
RESULTS: Transcriptomic profiling of the human dorsolateral prefrontal cortex from the Religious Order Study/Memory Aging Project (ROSMAP) cohort revealed the upregulation of cellular senescence transcriptome signatures in AD, which correlated with ABCA1 expression and oxysterol levels. Immunofluorescence and immunoblotting analyses confirmed increased lipofuscin-stained lipids and ABCA1 expression in AD brains and an association with mTOR phosphorylation. Discovery proteomics identified caveolin-1, a sensor of cellular cholesterol accumulation, as a key promoter of ABCA1 endolysosomal trafficking. Greater caveolin-1 expression was observed in APOE4-TR mouse models and AD human brains. Oxysterol induced mTORC1 activation and senescence were regulated by ABCA1 lysosomal trapping. Treatment of APOE4-TR mice with cyclodextrin reduced brain oxysterol levels, ABCA1 lysosome trapping, mTORC1 activation, and attenuated senescence and neuroinflammation markers. In human iPSC-derived astrocytes, the reduction of cholesterol by cyclodextrin attenuated inflammatory responses.
CONCLUSIONS: Oxysterol accumulation in APOE4 and AD induced ABCA1 and caveolin-1 expression, contributing to lysosomal dysfunction and increased cellular senescence markers. This study provides novel insights into how cholesterol metabolism accelerates features of brain cellular senescence pathway and identifies therapeutic targets to mitigate these processes.

Keywords:  ABCA1; Alzheimer’s disease; Caveolin-1; Cholesterol; Lysosome; Senescence

DOI:  https://doi.org/10.1186/s13024-025-00802-7
MethodsX. 2025 Jun;14 103175

Quantitative assessment of brain metabolism in mice using non-contrast MRI at 11.7T.

Xiuli Yang, Yuguo Li, Hanzhang Lu, Zhiliang Wei.

  Brain oxygen metabolism indicates the rate of energy consumption and is a potential marker of pathological changes. Positron emission tomography (PET) is the gold standard for measuring metabolic rates using radioactive tracers. However, its application in preclinical studies, particularly with rodent animals, is constrained by the need for arterial input function measurements and on-site cyclotron facilities for tracer preparation. As an alternative, non-invasive, non-contrast MRI techniques, such as T2-relaxation-under-spin-tagging (TRUST) and phase-contrast (PC) MRI, can be used for evaluating brain metabolism in vivo. This study outlines a step-by-step method for implementing TRUST and PC MRI in mice at 11.7T scanner. The proposed method yields non-invasive, non-contrast quantitative measurements of global brain metabolism in approximately 20 min, paving the way for broader applications in future pathophysiological studies.•Non-invasive and non-contrast assessment of brain metabolism in mice.•Quantitative measurement of metabolic rate in approximately 20 min.

Keywords:  Assessment of brain metabolism using non-contrast TRUST and PC MRI; Cerebral blood flow (CBF); Cerebral metabolic rate of oxygen (CMRO2); Fick principle; Phase contrast (PC); T2-relaxation-under-spin-tagging (TRUST)

DOI:  https://doi.org/10.1016/j.mex.2025.103175
J Neurochem. 2025 Feb;169(2): e70003

Transcript and Lipid Profile Alterations in Astrocyte-Neuron Mitochondrial Transfer Under Lipopolysaccharide Exposure: An In Vitro Study.

Yufei Kan, Hong Wang, Huaying Lin, Yongfa Li, Shuaijie Pei, Yan Cui, Keliang Xie, Hongguang Chen, Yonghao Yu.

  Sepsis-associated encephalopathy (SAE) is a brain dysfunction for which no effective therapy currently exists. Recent studies suggest that transferring mitochondria from astrocytes to neurons may benefit SAE patients, though the underlying mechanism remains unclear. We cultured astrocytes and neurons from mice in vitro. Astrocytes were stimulated with lipopolysaccharide (LPS) for 24 h, and the astrocyte-conditioned medium (ACM) was collected. Neuronal cultures were then treated with ACM or mitochondria-depleted ACM (mdACM) for further analysis. Mitochondrial transfer was examined under a fluorescence microscope. Western blotting analyzed the protein expression of genes related to apoptosis and mitochondrial metabolism. RNA sequencing and mass spectrometry were employed to investigate the mechanisms underlying mitochondrial transfer. Astrocyte-derived mitochondria migrated toward and connected with LPS-exposed neurons. The addition of ACM significantly attenuated LPS-induced alterations in the proteins linked to apoptosis and mitochondrial dynamics. RNA sequencing revealed notable alterations in the transcript profile of neurons upon ACM treatment, highlighting the involvement of mitochondria metabolism, inflammation, and apoptosis-related factors. Additionally, mitochondrial transfer modified the lipid composition of neurons, increasing phosphatidylserine levels, which correlated with neuroinflammation and enriched pathways related to cytokine and MAPK signaling. Our findings suggest that astrocyte-neuron mitochondrial transfer holds therapeutic potential for alleviating SAE, possibly through the anti-inflammatory effects of lipids, particularly phosphatidylserine.

Keywords:  astrocytes; lipidomics; mitochondrial transfer; neurons; sepsis‐associated encephalopathy; transcriptomics

DOI:  https://doi.org/10.1111/jnc.70003
Metab Brain Dis. 2025 Feb 07. 40(2): 121

Glutamate/GABA/glutamine ratios in intact and ischemia reperfusion challenged rat brain subregions, the effect of ischemic preconditioning.

Eva Baranovicova, Dagmar Kalenska, Jan Lehotsky.

  The proper function of the brain is entirely dependent on intact neurotransmission, where glutamate (Glu) and γ-aminobutyric acid (GABA) are the two most present neurotransmitters. Maintenance of these neurotransmitters pools is strictly relying on the de novo synthesis of glutamine in astrocytes. Cerebral ischemic events disrupt the balance in uptake and re-synthesis, altering Glu, GABA, and glutamine (Gln) levels. We focused on the determining of the ratios of glutamate, GABA and glutamine in the brain of rats in the intact state, the early changes and temporal development of changes towards the recovery after disruption of balance by global cerebral ischemia. Animals underwent 15 min of global cerebral ischemia, and changes in Glu/GABA/Gln ratios in the hippocampus, cortex, and cerebellum were assessed at 3 h, 24 h, and 72 h post-reperfusion using high-resolution NMR. Ischemic preconditioning was also used to induce tolerance. In an intact rat brain, glutamate level was about twice that of glutamine in all substructures, about sevenfold compared to GABA in the hippocampus and cortex, and almost eightfold compared to GABA in the cerebellum. There were three to four times as much glutamine compared to GABA. After severe cerebral ischemia, Glu/Gln as well as GABA/Gln ratios extensively dropped in early reperfusion (3 h) and gradually increased in 72 h reperfusion time, however, only the Glu/Gln ratio recovered to the level of controls. Glu/GABA ratio remained in all three reperfusion times over the level of control animals. We observed a decrease in glutathione NMR peak in brain tissue homogenates after ischemia. The obtained data suggest the accelerated accumulation of intraparenchymal glutamate after ischemia, which was even more pronounced in the preconditioned animals three days after an ischemic event. The postischemic GABA level restoration did not achieve the level before ischemia in 72 h reperfusion, which could be one of the limiting factors in the complete postischemic GABA transmission recovery. Presented data may be of advantage not only when comparing glutamate and GABA homeostasis and neurotransmission, but also for glutamine reserve display as neurotransmitter precursor and ammonia transfer buffer in glutamate/GABA/glutamine cycle within the intact brain substructures as well after ischemic insult in rats.

Keywords:  Cerebral ischemia; GABA; Glutamate; Glutamine; Ischemic preconditioning; NMR metabolomics; Rat

DOI:  https://doi.org/10.1007/s11011-024-01511-8
Cell Metab. 2025 Jan 29. pii: S1550-4131(24)00491-1. [Epub ahead of print]

Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.

Won Dong Lee, Daniel R Weilandt, Lingfan Liang, Michael R MacArthur, Natasha Jaiswal, Olivia Ong, Charlotte G Mann, Qingwei Chu, Craig J Hunter, Rolf-Peter Ryseck, Wenyun Lu, Anna M Oschmann, Alexis J Cowan, Tara A TeSlaa, Caroline R Bartman, Cholsoon Jang, Joseph A Baur, Paul M Titchenell, Joshua D Rabinowitz.

  Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.

Keywords:  HCAR1 signaling; TCA cycle; competitive catabolism; diabetes mellitus; insulin resistance; insulin signaling; lactate metabolism; metabolic flux; metabolic homeostasis; quantitative modeling

DOI:  https://doi.org/10.1016/j.cmet.2024.12.009
Brain Behav Immun Health. 2025 Feb;43 100938

Lipid mediators in post-mortem brain samples from patients with Alzheimer's disease: A systematic review.

Aidan D Tyrrell, Giulia Cisbani, Mackenzie E Smith, Chuck T Chen, Yue-Tong Chen, Raphael Chouinard-Watkins, Kathryn E Hopperton, Ameer Y Taha, Richard P Bazinet.

  A proposed contributor to Alzheimer's disease (AD) pathology is the induction of neuroinflammation due to tau and beta-amyloid protein accumulation causing neuronal injury and dysfunction. Dysregulation of lipid mediators derived from polyunsaturated fatty acids may contribute to this inflammatory response in the brain of patients with AD, yet the literature has not yet been systematically reviewed. A systematic search was conducted in Medline, Embase and PsychINFO for articles published up to April 22, 2024. Papers were included if they measured levels of lipid mediators and/or enzymes involved in their production in post-mortem brain samples from patients with AD and control without neurological disease. A total of 50 relevant studies were identified. Despite heterogeneity in the results, pro-inflammatory lipid mediators, including 5-, 11-, 12- and 15-hydroxyeicosatetraenoic acid oxylipins and prostaglandin D2, were significantly higher, while anti-inflammatory lipoxin A4 and DHA-derived docosanoids were significantly lower in brains of patients with AD compared to control (16 studies). Thirty-seven articles reported on enzymes, with 32 reporting values for enzyme level changes between AD and controls. Among the 32 articles, the majority reported on levels of cyclooxygenase (COX) (18/32), with fewer studies reporting on phospholipase (8/32), lipoxygenase (LOX) (4/32) and prostaglandin E synthase (4/32). Enzyme levels also exhibited variability in the literature, with a trend towards elevated expression of enzymes involved in the pro-inflammatory response, including COX and LOX enzymes. Overall, these results are consistent with the involvement of neuroinflammation in the pathogenesis of AD measured by lipid mediators. However, the specific contribution of each lipid metabolite and enzymes to either the progression or persistence of AD remains unclear, and more research is required.

Keywords:  Alzheimer's disease; Lipid mediators; Neuroinflammation; Post-mortem

DOI:  https://doi.org/10.1016/j.bbih.2024.100938
Neurobiol Dis. 2025 Feb 01. pii: S0969-9961(25)00043-9. [Epub ahead of print]206 106827

Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice.

Alexandra F Putka, Varshasnata Mohanty, Stephanie M Cologna, Hayley S McLoughlin.

  Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia and belongs to the family of nine diseases caused by a polyglutamine expansion in the disease-causing protein. In SCA3, a polyglutamine expansion in ATXN3 causes neuron loss in disease-vulnerable brain regions, resulting in progressive loss of coordination and ultimately death. There are no disease-modifying or preventative treatments for this uniformly fatal disorder. Recent studies demonstrate prominent white matter atrophy and microstructural alterations in disease-vulnerable brain regions of SCA3 patients and mouse models. However, the major constituent of white matter - lipids - remains understudied in SCA3. In this study, we conducted the first unbiased investigation of brain lipids in SCA3, focusing on the disease-vulnerable cerebellum of SCA3 postmortem patients and mouse models. Liquid chromatography-mass spectrometry uncovered widespread lipid reductions in patients with SCA3. Lipid downregulation was recapitulated in early- to mid-stage mouse models of SCA3, including transgenic YACQ84 and Knock-in Q300 mice. End-stage Knock-in Q300 mice displayed a progressive reduction in lipid content, highlighting targets that could benefit from early therapeutic intervention. In contrast, Atxn3-Knock-out mice showed mild lipid upregulation, emphasizing a toxic gain-of-function mechanism underlying lipid downregulation in SCA3. We conclude that lipids are significantly altered in SCA3 and establish a platform for continued exploration of lipids in disease through interactive data visualization websites. Pronounced reductions in myelin-enriched lipids suggest that lipid dysregulation could underlie white matter atrophy in SCA3. This study establishes the basis for future work elucidating the mechanistic, biomarker, and therapeutic potential of lipids in SCA3.

Keywords:  Cholesterol; Lipidomics; Molecular mechanism; Neurodegenerative disease; Oligodendrocyte; Sulfatide

DOI:  https://doi.org/10.1016/j.nbd.2025.106827
bioRxiv. 2025 Jan 23. pii: 2025.01.20.633997. [Epub ahead of print]

Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.

Sara Wong, Katherine R Bertram, Nidhi Raghuram, Thomas Knight, Adam L Hughes.

Lipid saturation is a key determinant of membrane function and organelle health, with changes in saturation triggering adaptive quality control mechanisms to maintain membrane integrity. Among cellular membranes, the mitochondrial outer membrane (OMM) is an important interface for many cellular functions, but how lipid saturation impacts OMM function remains unclear. Here, we show that increased intracellular unsaturated fatty acids (UFAs) remodel the OMM by promoting the formation of multilamellar mitochondrial-derived compartments (MDCs), which sequester proteins and lipids from the OMM. These effects depend on the incorporation of UFAs into membrane phospholipids, suggesting that changes in membrane bilayer composition mediate this process. Furthermore, elevated UFAs impair the assembly of the OMM protein translocase (TOM) complex, with unassembled TOM components captured into MDCs. Collectively, these findings suggest that alterations in phospholipid saturation may destabilize OMM protein complexes and trigger an adaptive response to sequester excess membrane proteins through MDC formation.
Significance Statement: Mitochondrial-derived compartments are multilamellar structures that sequester protein and lipids of the outer mitochondrial membrane in response to metabolic and membrane perturbations, but it is largely unknown how membrane fluidity influences this pathway.Increased levels of unsaturated phospholipids may disrupt the TOM complex, a large multi-subunit complex on the outer mitochondrial membrane, to promote the formation of mitochondrial-derived compartments, while increased levels of saturated phospholipids inhibits formation of mitochondrial-derived compartments.These findings reveal a link between phospholipid composition and protein stress in driving mitochondrial-derived compartment biogenesis, and thus mitochondrial quality control.

DOI: https://doi.org/10.1101/2025.01.20.633997
Aging (Albany NY). 2025 Feb 06. 17

Mitochondrial dysfunction, iron accumulation, lipid peroxidation, and inflammasome activation in cellular models derived from patients with multiple sclerosis.

Raquel García-Salas, Paula Cilleros-Holgado, Anna Di Spirito, David Gómez-Fernández, Rocío Piñero-Pérez, José Manuel Romero-Domínguez, Mónica Álvarez-Córdoba, Diana Reche-López, Ana Romero-González, Alejandra López-Cabrera, José Antonio Sánchez-Alcázar.

  Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Despite advancements in managing relapsing active illness, effective treatments for the irreversible progressive decline in MS remain limited. Research employing skin fibroblasts obtained from patients with neurological disorders revealed modifications in cellular stress pathways and bioenergetics. However, research using MS patient-derived cellular models is scarce. In this study, we collected fibroblasts from two MS patients to investigate cellular pathological alterations. We observed that MS fibroblasts showed a senescent morphology associated with iron/lipofuscin accumulation and altered expression of iron metabolism proteins. In addition, we found increased lipid peroxidation and downregulation of antioxidant enzymes expression levels in MS fibroblasts. When challenged against erastin, a ferroptosis inducer, MS fibroblasts showed decreased viability, suggesting increased sensitivity to ferroptosis. Furthermore, MS fibroblasts presented alterations in the expression levels of autophagy-related proteins. Interestingly, these alterations were associated with mitochondrial dysfunction and inflammasome activation. These findings were validated in 7 additional patient-derived cell lines. Our findings suggest that the underlying stress phenotype of MS fibroblasts may be disease-specific and recapitulate the main cellular pathological alterations found in the disease such as mitochondrial dysfunction, iron accumulation, lipid peroxidation, inflammasome activation, and pro-inflammatory cytokine production.

Keywords:  inflammasome; iron accumulation; lipid peroxidation; mitochondrial dysfunction; multiple sclerosis

DOI:  https://doi.org/10.18632/aging.206198
J Theor Biol. 2025 Jan 30. pii: S0022-5193(25)00015-3. [Epub ahead of print]602-603 112049

A mathematical model of microglia glucose metabolism and lactylation with positive feedback.

Kamila Larripa, Anca Rǎdulescu.

  In this paper, we present and analyze a model for metabolism and lactylation in a single microglia. The model includes positive feedback from lactylation in the glycolytic pathway, and links metabolism and inflammation. Specific pathways include the transition of glucose to pyruvate to lactate in a microglia, as well as the gradient transport of glucose and lactate into and out of the cell. Additionally, the upregulation of certain pathways by either epigenetic modification or the inflammatory response are included. Bifurcation and sensitivity analyses demonstrate the importance of key parameters and pathways in the model, specifically the role of lactylation. Our model is validated by qualitatively reproducing recent in vitro experiments in which exogenous glucose and lactate are modified.

Keywords:  Bifurcation analysis; Differential equations; Feedback; Metabolism; Microglia

DOI:  https://doi.org/10.1016/j.jtbi.2025.112049
Epilepsia Open. 2025 Feb 07.

Practical experience and challenges in nutritional management of glucose transporter 1 deficiency syndrome: Provider survey results.

Ketogenic Dietitians Research Network

  Ketogenic diets (KDs) are recommended as precision therapy for glucose transporter 1 deficiency syndrome (GLUT-1 DS) but there are no recommendations for optimal implementation in this population. We administered an online survey targeting clinicians with experience implementing KDs in GLUT-1 DS, focusing on diet selection, initiation, and management. Respondents were primarily experienced registered dietitian nutritionists (RDNs) from 34 centers in 10 countries. Most reported a preference for carbohydrate counting or ratios under 3:1. KD-related laboratory monitoring (including blood ketones) and vitamin/mineral supplementation did not differ for GLUT-1 DS patients compared to the epilepsy population. Routine use of exogenous ketones was not endorsed for improved ketosis, whereas MCT oil is a commonly used supplement. Respondents overwhelmingly endorsed discussing and implementing gastrostomy feedings to support continued dietary therapy when medically indicated. Most but not all providers (80%) were familiar with the 2020 consensus guidelines. Our survey demonstrates practice variability among experienced dietitians, particularly in diet type and ratio. Identified challenges carry clinical significance, as the diet is a precision therapy in GLUT1-DS. Further research is needed to examine the outcomes of different approaches to KDs in GLUT-1 DS before consensus about the most effective interventions can be reached. PLAIN LANGUAGE SUMMARY: Glucose transporter deficiency syndrome is a genetic condition caused by an inability to move sugar (glucose) into the brain, which is needed for proper brain function. Ketogenic diets (low in carbohydrate and high in fat) are the established treatment to help control symptoms. Although the diet is effective, it can be challenging. To understand these challenges, we surveyed experts in ketogenic diet management and found significant variability regarding specifics of how the diet is managed. More research is needed before one approach can be endorsed as most effective.

Keywords:  GLUT1; SLC21A; glucose transporter 1 deficiency; ketogenic diet; nutritional management

DOI:  https://doi.org/10.1002/epi4.13135
Mitochondrion. 2025 Jan 31. pii: S1567-7249(25)00004-2. [Epub ahead of print] 102007

Novel intronic variant in NDUFS7 gene results in mitochondrial complex I assembly defect with early basal ganglia and midbrain involvement with progressive neuroimaging findings.

Jaakko Oikarainen, Reetta Hinttala, Naemeh Nayebzadeh, Salla M Kangas, Katariina Mankinen, Elisa Rahikkala, Hannaleena Kokkonen, Päivi Vieira, Maria Suo-Palosaari, Johanna Uusimaa.

  Leigh syndrome is the most common phenotype of mitochondrial disorders in children. This study demonstrates clinical, neuroradiological, and molecular genetic findings in siblings with Leigh syndrome and isolated complex I assembly defect associated with intronic c.16 + 5G > A variant in the NDUFS7 gene. Whole exome sequencing was carried out to identify the causative variant. The gene and protein expression of NDUFS7 were studied using patient-derived fibroblasts. Assembly of mitochondrial respiratory chain enzymes was analyzed using Blue Native PAGE. This study shows that the NDUFS7 c.16 + 5G > A variant (rs375282422) has a causative role in Leigh syndrome. Evolution of neuroimaging findings related to this gene variant are demonstrated.

Keywords:  Intronic variant; Leigh syndrome; Mitochondrial; NDUFS7; Neuroimaging; Rare variant

DOI:  https://doi.org/10.1016/j.mito.2025.102007
J Biosci. 2025 ;pii: 9. [Epub ahead of print]50

Prenatal protein deficiency causes age-specific alteration in number and distribution of inhibitory neurons in the somatosensory cortex during early postnatal development.

Arti Kumari, V Rema, Neeraj Jain.

Prenatal protein deficiency causes behavioral and cognitive dysfunctions in children. The deficits could be caused by altered acquisition and processing of sensory information in the brain. Although GABAergic neurons are the key regulators of neuronal activity, the effect of prenatal protein deficiency on GABA neurons in the brain is largely unknown. We fed pregnant mice diets with one-third (7%) or half (10%) the normal protein requirement (20% protein). After birth, the pups were fostered with normally fed lactating females. We used transgenic mice to show that protein deficiency in pregnant dams fed a 7% protein diet affected the number and distribution of GABA neurons in the somatosensory barrel cortex and individual cortical layers during early postnatal development of pups. If the mothers were fed a 10% protein diet, the effects on GABA neurons were much less. Development of barrels was also affected in pups born to mothers fed the 7% protein diet, but not the 10% group. In addition, high protein deficiency, i.e., the 7% protein diet, affected conception, hampered gestational weight gain, induced resorption of embryos, reduced litter sizes, and increased cannibalism, which was not observed in females on 10% protein diet.
Curr Med Chem. 2025 Jan 30.

Lipid Biochemistry and its Role in Human Diseases.

Amine Nehaoua, Amin Gasmi, Asma Gasmi Benahmed, Sadaf Noor, Geir Bjørklund.

  Lipids play a variety of roles in living systems. They are a source of extremely high energy and a part of almost all signaling and biological processes. Despite the liver being the hub of lipid metabolism, lipid metabolism occurs across the human body. Any perturbation in the lipid metabolism or lipid storage systems can lead to diseases or disorders that can hamper the normal functioning of the human body. Lipids have been explored for their role in cancers. The intake of saturated fatty acids has been found to increase the metastasis and growth of cancerous cells. The role of lipids has also been studied in brain diseases. In Tay-Sachs disease, the inability to metabolize GM2 ganglioside alters normal nerve cell functioning. Similarly, lipids also play critical roles in Parkinson's and Alzheimer's disease. Moreover, atherosclerosis is a leading cause of cardiovascular diseases and brain stroke. Dyslipidemia or excess fatty acids is a leading cause of non-alcoholic fatty liver disease, insulin resistance, and diabetes mellitus. Dyslipidemia also leads to jaundice, which, in turn, can seriously damage the kidneys. This review focuses on the various human diseases occurring because of lipid metabolism.

Keywords:  Lipids; atherosclerosis; cancers; dyslipidemia.; human diseases; lipid metabolism

DOI:  https://doi.org/10.2174/0109298673351452241220071215
Microbiol Res. 2025 Jan 31. pii: S0944-5013(25)00036-9. [Epub ahead of print]293 128080

The 1-acylglycerol-3-phosphate acyltransferase Slc1 is required to regulate mitochondria and lipid droplets.

Chenhui Zhao, Ke Liu, Yifan Wu, Shuaijie Yan, Jiajia He, Chuanhai Fu.

  Mitochondria are organelles involved in energy metabolism and biosynthesis. As the metabolites released from mitochondria are raw materials used for lipid synthesis, mitochondria also play important roles in lipid metabolism. Here we report that Slc1, a 1-acylglycerol-3-phosphate O-acyltransferase in the fission yeast Schizosaccharomyces pombe, is required to maintain tubular mitochondrial morphology and normal mitochondrial functions. The absence of Slc1 causes mitochondrial fragmentation, increases mitochondrial fission frequency, reduces mitochondrial respiration, and slows down nitrogen starvation-induced mitophagy. In addition, the absence of Slc1 significantly increases the protein level of Ptl2, which is the triacylglycerol lipase localized on lipid droplets. The phenotypes caused by the absence of Slc1 depend on its acyltransferase enzymatic activity. Therefore, our study uncovers new roles of a lipid synthesis enzyme Slc1 in regulating mitochondria and lipid droplets.

Keywords:  1-acylglycerol-3-phosphate O-acyltransferase; Lipid droplet; Mitochondria; Mitophagy; Schizosaccharomyces pombe

DOI:  https://doi.org/10.1016/j.micres.2025.128080
Cell Mol Life Sci. 2025 Feb 07. 82(1): 72

Charcot Marie Tooth disease pathology is associated with mitochondrial dysfunction and lower glutathione production.

Nafisa R Komilova, Plamena R Angelova, Elisa Cali, Annarita Scardamaglia, Ulugbek Z Mirkhodjaev, Henry Houlden, Noemi Esteras, Andrey Y Abramov.

  Charcot Marie Tooth (CMT) or hereditary motor and sensory neuropathy is a heterogeneous neurological disorder leading to nerve damage and muscle weakness. Although multiple mutations associated with CMT were identified, the cellular and molecular mechanisms of this pathology are still unclear, although most of the subtype of this disease involve mitochondrial dysfunction and oxidative stress in the mechanism of pathology. Using patients' fibroblasts of autosomal recessive, predominantly demyelinating form of CMT-CMT4B3 subtype, we studied the effect of these mutations on mitochondrial metabolism and redox balance. We have found that CMT4B3-associated mutations decrease mitochondrial membrane potential and mitochondrial NADH redox index suggesting an increase rate of mitochondrial respiration in these cells. However, mitochondrial dysfunction had no profound effect on the overall levels of ATP and on the energy capacity of these cells. Although the rate of reactive oxygen species production in mitochondria and cytosol in fibroblasts with CMT4B3 pathology was not significantly higher than in control, the level of GSH was significantly lower. Lower level of glutathione was most likely induced by the lower level of NADPH production, which was used for a GSH cycling, however, expression levels and activity of the major NADPH producing enzyme Glucose-6-Phosphate Dehydrogenase (G6PDH) was not altered. Low level of GSH renders the fibroblast with CMT4B3 pathology more sensitive to oxidative stress and further treatment of cells with hydroperoxide increases CMT patients' fibroblast death rates compared to control. Thus, CMT4B3 pathology makes cells vulnerable to oxidative stress due to the lack of major endogenous antioxidant GSH.

Keywords:  ATP; CMT (Charcot Marie Tooth disease); Glutathione; Mitochondria; Reactive oxygen species

DOI:  https://doi.org/10.1007/s00018-025-05612-0
Neoreviews. 2025 Feb 01. 26(2): e100-e114

Applications of Metabolomics and Lipidomics in the Neonatal Intensive Care Unit.

Stanford Metabolic Health Center

The metabolome and lipidome comprise the thousands of molecular compounds in an organism. Molecular compounds consist of the upstream metabolic components of intracellular reactions or the byproducts of cellular pathways. Molecular and biochemical perturbations are associated with disorders in newborns and infants. The diagnosis of inborn errors of metabolism has relied on targeted metabolomics for several decades. Newer approaches offer the potential to identify novel biomarkers for common diseases of the newborn and infant. They may also elucidate novel predictive or diagnostic measures for a variety of health trajectories. Here, we review the relevance of the metabolome and lipidome for common disorders and highlight challenges and opportunities for future investigations.

DOI: https://doi.org/10.1542/neo.26-2-011
Sci Rep. 2025 Feb 06. 15(1): 4540

MCU expression in hippocampal CA2 neurons modulates dendritic mitochondrial morphology and synaptic plasticity.

Katy E Pannoni, Quentin S Fischer, Renesa Tarannum, Mikel L Cawley, Mayd M Alsalman, Nicole Acosta, Chisom Ezigbo, Daniela V Gil, Logan A Campbell, Shannon Farris.

  Neuronal mitochondria are diverse across cell types and subcellular compartments in order to meet unique energy demands. While mitochondria are essential for synaptic transmission and synaptic plasticity, the mechanisms regulating mitochondria to support normal synapse function are incompletely understood. The mitochondrial calcium uniporter (MCU) is proposed to couple neuronal activity to mitochondrial ATP production, which would allow neurons to rapidly adapt to changing energy demands. MCU is uniquely enriched in hippocampal CA2 distal dendrites compared to proximal dendrites, however, the functional significance of this layer-specific enrichment is not clear. Synapses onto CA2 distal dendrites readily express plasticity, unlike the plasticity-resistant synapses onto CA2 proximal dendrites, but the mechanisms underlying these different plasticity profiles are unknown. Using a CA2-specific MCU knockout (cKO) mouse, we found that MCU deletion impairs plasticity at distal dendrite synapses. However, mitochondria were more fragmented and spine head area was diminished throughout the dendritic layers of MCU cKO mice versus control mice. Fragmented mitochondria might have functional changes, such as altered ATP production, that could explain the structural and functional deficits at cKO synapses. Differences in MCU expression across cell types and circuits might be a general mechanism to tune mitochondrial function to meet distinct synaptic demands.

Keywords:  Dendrites; Hippocampal CA2; Mitochondria; Mitochondrial calcium uniporter; Spines; Synaptic plasticity

DOI:  https://doi.org/10.1038/s41598-025-85958-4
Cell. 2025 Jan 10. pii: S0092-8674(24)01420-X. [Epub ahead of print]

Rhodoquinone carries electrons in the mammalian electron transport chain.

Jonathan Valeros, Madison Jerome, Tenzin Tseyang, Paula Vo, Thang Do, Diana Fajardo Palomino, Nils Grotehans, Manisha Kunala, Alexandra E Jerrett, Nicolai R Hathiramani, Michael Mireku, Rayna Y Magesh, Batuhan Yenilmez, Paul C Rosen, Jessica L Mann, Jacob W Myers, Tenzin Kunchok, Tanner L Manning, Lily N Boercker, Paige E Carr, Muhammad Bin Munim, Caroline A Lewis, David M Sabatini, Mark Kelly, Jun Xie, Michael P Czech, Guangping Gao, Jennifer N Shepherd, Amy K Walker, Hahn Kim, Emma V Watson, Jessica B Spinelli.

  Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.

Keywords:  electron transport chain; hypoxia; ischemia; metabolism; mitochondria; rhodoquinone

DOI:  https://doi.org/10.1016/j.cell.2024.12.007
bioRxiv. 2025 Jan 22. pii: 2025.01.17.633669. [Epub ahead of print]

Coupling between membrane undulations and lipid curvature leads to transient local enrichment of cardiolipin in mitochondrial membranes.

Christopher T Lee, Kailash Venkatraman, Itay Budin, Padmini Rangamani.

Organelles such as mitochondria have characteristic shapes that are critical to their function. Recent efforts have revealed that the curvature contributions of individual lipid species can be a factor in the generation of membrane shape in these organelles. Inspired by lipidomics data from yeast mitochondrial membranes, we used Martini coarse-grained molecular dynamics simulations to investigate how lipid composition facilitates membrane shaping. We found that increasing lipid saturation increases bending rigidity while reducing the monolayer spontaneous curvature. We also found that systems containing cardiolipin exhibited decreased bending rigidity and increased spontaneous curvature when compared to bilayers containing its precursor phosphatidylglycerol. This finding contradicts some prior experimental results that suggest that bilayers containing tetraoleoyl cardiolipin have greater rigidity than dioleoyl phosphatidylcholine bilayers. To investigate this discrepancy, we analyzed our simulations for correlations between lipid localization and local curvature. We found that there are transient correlations between curved lipids such as cardiolipin (CDL) and phosphatidylethanolamine (PE) and curvature; these interactions enrich specific bilayer undulatory modes and cause bilayer softening. Furthermore, we show that curvature-localization some lipids such as cardiolipin can influence lipids in the opposing leaflet. These observations add to the emerging evidence that lipid geometric features give rise to local interactions, which can cause membrane compositional heterogeneities. The cross-talk between composition-driven tuning of membrane properties and membrane shape has implications for membrane organization and its related functions.

DOI: https://doi.org/10.1101/2025.01.17.633669