bims-medebr 2025-08-24 papers

Brain. 2025 Aug 20. pii: awaf300. [Epub ahead of print]

Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.

Defects in mitochondrial dynamics are a common cause of Charcot-Marie-Tooth disease (CMT), while primary deficiencies in the mitochondrial respiratory chain (MRC) are rare and atypical for this etiology. This study aims to report COX18 as a novel CMT-causing gene. This gene encodes an assembly factor of mitochondrial Complex IV (CIV) that translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane. Exome sequencing was performed in four affected individuals from three families. The patients and available family members underwent thorough neurological and electrophysiological assessment. The impact of one of the identified variants on splicing, protein levels, and mitochondrial bioenergetics was investigated in patient-derived lymphoblasts. The functionality of the mutant protein was assessed using a Proteinase K protection assay and immunoblotting. Neuronal relevance of COX18 was assessed in a Drosophila melanogaster knockdown model. Exome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435-6A>G in COX18 in two siblings with early-onset progressive axonal sensory-motor peripheral neuropathy. By querying external databases, we identified two additional families with rare deleterious biallelic variants in COX18. All eight affected individuals presented with axonal CMT and some patients also exhibited central nervous system symptoms, such as dystonia and spasticity. Functional characterization of the c.435-6A>G variant demonstrated that it leads to the expression of an alternative transcript that lacks exon 2, resulting in a stable but defective COX18 isoform. The mutant protein impairs CIV assembly and activity, leading to a reduction in mitochondrial membrane potential. Downregulation of the COX18 homolog in Drosophila melanogaster displayed signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons. Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without central nervous system involvement. These findings emphasize the significance of peripheral neuropathy within the spectrum of primary mitochondrial disorders and the role of mitochondrial CIV in the development of CMT. Our research has important implications for the diagnostic workup of CMT patients.

Keywords: CMT; complex IV deficiency; cytochrome c oxidase assembly factor 18

DOI: https://doi.org/10.1093/brain/awaf300

medRxiv. 2025 Aug 12. pii: 2025.08.08.25333304. [Epub ahead of print]

Specific Lipid Abnormalities Are Inherently Associated with Late-Onset Alzheimer's Disease.

Bruce M Cohen, Eunjung Koh, Kandice R Levental, Ilya Levental, Kai-Christian Sonntag.

INTRODUCTION: Lipid abnormalities have been observed in brain, CSF, and blood in association with late-onset Alzheimer's disease (LOAD). It is unknown which abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived neural lines.
METHODS: iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Lipidomics analyses were performed on whole cell and mitochondrial extracts.
RESULTS: Large reductions in cholesterol esters (CE) and imbalances in fatty acids (FA) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids.
DISCUSSION: The findings identify abnormalities in CE and FA as likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD.

DOI: https://doi.org/10.1101/2025.08.08.25333304

bioRxiv. 2025 Aug 12. pii: 2025.08.08.669302. [Epub ahead of print]

High-resolution quantification of metabolic heat output from individual live Drosophila brains.

Kanishka Panda, Rohith Mittapally, Qianqian Chen, Akshay Bhaskaran, Pramod Reddy, Edgar Meyhofer, Swathi Yadlapalli.

Quantitative insights into brain metabolism are essential for advancing our understanding of the energy dynamics in the brain. However, current approaches to tracking brain metabolism, such as metabolic profiling, offer only static snapshots of metabolite levels and fall short in capturing real-time energy fluxes. Here, we present the first direct, quantitative measurement of metabolic output from individual, live explanted brains of Drosophila melanogaster using a high-resolution biocalorimeter capable of detecting nanowatt-scale metabolic changes, while maintaining brain viability via continuous buffer perfusion. Using this platform, we measured an average metabolic output of ∼256 nW per brain in female, 10-day-old Drosophila flies. Notably, female brains exhibited significantly higher metabolic activity than male brains at a young age (10-day-old). Furthermore, in parkin mutants-used to model Parkinson's disease-homozygous mutant brains showed a ∼15% reduction in metabolic output relative to heterozygous controls, consistent with impaired mitochondrial function. We further extended our measurements to other Drosophila tissues, demonstrating that mass-normalized metabolic rates of ovaries and testes are ∼2.5-fold lower compared to brains in Drosophila , highlighting the brain's exceptional energy demands. This platform enables real-time, quantitative brain bioenergetics studies and is adaptable to tissue organoids and drug screening, offering new avenues for investigating aging, neurodegeneration, and metabolism-driven disease mechanisms.

DOI: https://doi.org/10.1101/2025.08.08.669302

Open Biol. 2025 Aug;15(8): 250198

Systemic analyses show that the biosynthesis and spatial distribution of fatty acids, triglycerides and lipids differed in male and female mice and humans.

Samuel Furse, Samuel Virtue, Isabel Huang-Doran, Antonio Vidal-Puig, Davide Chiarugi, Philip C Stevenson, Stuart G Snowden, Albert Koulman.

Recent work has shown that the prevalence and character of metabolic diseases differs between male and female mammals. This strongly suggests that the control mechanisms that govern, for example lipid metabolism, differ between the sexes. If true, a one-size-fits-all approach to treating metabolic disease will not be effective in all patients. We tested three hypotheses to understand how the lipid metabolism of male and female mammals may differ. First, whether endogenous fatty acid biosynthesis differed between tissues in the same male and female mice. Second, whether the system-level control of lipid pathways differed between the sexes. Third, whether lipid composition differs between males and females at a population level. We found that fatty acid biosynthesis was distinct in male and female mice across tissues. Systemic control of phospholipid and triglyceride metabolism also differed between the sexes. A human population showed that both phospholipid and triglyceride metabolism differed between males and females.

Keywords: biosynthesis; control; differs; females; lipids; metabolism

DOI: https://doi.org/10.1098/rsob.250198

Neuroscience. 2025 Aug 16. pii: S0306-4522(25)00846-2. [Epub ahead of print]

[3H]T-401 binding to monoacylglycerol lipase (MAGL) in the brains of patients and mice with temporal lobe epilepsy.

Sanjay S Aripaka, Burcu A Pazarlar, Lars H Pinborg, Karen Bonde-Larsen, Francois Gastambide, Benny Bang-Andersen, Jesper F Bastlund, Jens D Mikkelsen.

Monoacylglycerol lipase (MAGL) inhibitors are considered as drug candidates for epilepsy. In order to determine the level of MAGL and evaluate changes in the epileptic brain, we have validated and used autoradiography and the MAGL radiotracer [3H]T-401 on resected temporal neocortex specimens obtained from patients with temporal lobe epilepsy and in brains from mice with chronic reoccurring seizures. Saturation experiments revealed a KD around 4 nM for the human temporal cortex and 7 nM for the mouse brain. In the human brain, binding of [3H]T-401 was detected mostly in the grey matter, and in the subcortical white matter in lower amounts. The levels were strongly correlated in the two cortical compartments. The level of [3H]T-401 binding in the human temporal cortex varied about a 4-fold among the patients, but was not correlated to either epilepsy duration or the age of the patients. In the epileptic mouse brain, a significant reduction was observed bilaterally in the hippocampus, as well as in other cortical regions, including the temporal cortex. Interestingly, a highly significant negative correlation was seen between MAGL and binding to the translocator protein 18 kDa (TSPO) expressed in glia. These data support the presence of MAGL in neuronal and non-neuronal cells, and indicate that MAGL levels in the brains of either patients with epilepsy or mice after intra-hippocampal kainic acid injection are reduced not only in the epileptic zone in the hippocampus, but more widespread in the brain.

DOI: https://doi.org/10.1016/j.neuroscience.2025.08.016

Sci Rep. 2025 Aug 19. 15(1): 30464

Measuring cerebral hemodynamics and oxygen metabolism indices using NIR-TRS in premature infants from birth to term-equivalent age.

Shonosuke Nara, Midori Nishibata, Maria Nishibukuro, Naofumi Hanyu, Soken Go, Hironobu Okuno, Shinji Nakamura, Takashi Kusaka, Gaku Yamanaka.

Central nervous system development influences the neurological prognosis of premature infants, and their management may be better guided by the evaluation of the oxygen supply-demand balance in brain tissue. Near-infrared time-resolved spectroscopy (NIR-TRS) can measure cerebral oxygen metabolism indices, including cerebral blood volume (CBV), as absolute values. Cerebral hemoglobin oxygen saturation (ScO2) and the cerebral tissue oxygen extraction rate (cFTOE), but not CBV, have been reported in premature infants. Here, we used NIR-TRS to evaluate the longitudinal changes in these indices, including CBV, in 26 extremely premature infants born at < 30 weeks' gestation without intracranial hemorrhage. ScO2 was very slightly negatively correlated with postnatal week (r = - 0.19, p < 0.001). The cFTOE increased with postnatal week (r = 0.37, p < 0.001) and postconceptional week (r = 0.81, p < 0.001) while CBV decreased with postnatal week (r = - 0.34, p < 0.001) and postconceptional week (r = - 0.90, p < 0.001). This study is the first to prospectively evaluate changes in CBV after birth in preterm infants without intracranial hemorrhage. Our results show that the cerebral oxygen demand of preterm infants increases with postnatal week but that the growth of the cerebral vascular bed may be delayed.

Keywords: Cerebral blood volume; Cerebral tissue hemoglobin oxygen saturation; Near-infrared time-resolved spectroscopy; Preterm infant

DOI: https://doi.org/10.1038/s41598-025-15548-x