bims-mitmed 2025-10-12 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–10–12
twenty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
The energy resistance principle.
Biallelic NDUFA9 variants cause a progressive neurodevelopmental disorder with prominent dystonia and mitochondrial complex I deficiency.
Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.
Exploring multiorgan mitochondrial dysfunction in the switch toward progressive MASLD in AMLN mice.
Multifaceted mitochondria in innate immunity.
The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.
First approved drug for mitochondrial disease raises hopes for more.
Outcomes misaligned in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): implications for trial design.
Quantitative cellular characterization of extracellular mitochondria uptake and delivery.
Placental mTOR signalling links mitochondrial dysfunction, nutrient transport and neonatal beta cell perturbations in mice.
Genotype-Phenotype Correlations in Chinese Pediatric Patients With Single Large-Scale Mitochondrial DNA Deletion Disorders.
Markers of mitochondrial function and oxidative metabolism in skeletal muscle do not display intrinsic circadian regulation in female mice.
STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
Mitochondrial Ca2+ uniporter haploinsufficiency leads to sexually dimorphic redox imbalance and metabolic remodelling in the mouse brain.
Mitochondrial Lon Peptidase 1 Controls Diaphragm and Lung Development in a Context-Dependent Manner.
Activity-dependent citrate dynamics in neurons.
Mitochondrial dysfunction and aging can be alleviated by modulating calcineurin and cardiolipin dynamics following stroke.
Spatiotemporal crosstalk among mitochondrial dynamics, NLRP3 inflammasome activation, and histone lactylation drives α-synuclein pathology in prodromal Parkinson's disease.
Distinct maternal DNA methylation associations with gestational age at early and late-mid term pregnancy in a low- and middle-income country: evaluation of biological, genetic, and psychosocial contributors.
Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.
The secreted metabolite sensor CtBP2 links metabolism to healthy lifespan.

Science. 2025 Oct 09. 390(6769): 156-163

Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.

Michele Frison, Brandon S Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D Ryall, Camilla Lyons, Stephen P Burr, Malwina Prater, Lyuba V Bozhilova, Angelos Glynos, James B Stewart, Nick S Jones, Marcos R Chiaratti, Patrick F Chinnery.

Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.

DOI: https://doi.org/10.1126/science.adr5438
Cell Metab. 2025 Oct 06. pii: S1550-4131(25)00387-0. [Epub ahead of print]

The energy resistance principle.

Martin Picard, Nirosha J Murugan.

  Living organisms are physical-energetic systems that must obey simple principles guiding energy transformation across physical and temporal scales. The energy resistance principle (ERP) describes behavior and transformation of energy in the carbon-based circuitry of biology. We show how energy resistance (éR) is the fundamental property that enables transformation, converting into useful work the unformed energy potential of food-derived electrons fluxing toward oxygen. Although éR is required to sustain life, excess éR directly causes reductive and oxidative stress, heat, inflammation, molecular damage, and information loss-all hallmarks of disease and aging. We discuss how disease-causing stressors elevate éR and circulating growth differentiation factor 15 (GDF15) levels, whereas sleep, physical activity, and restorative interventions that promote healing minimize éR. The ERP is a testable general framework for discovering the modifiable bioenergetic forces that shape development, aging, and the dynamic health-disease continuum.

Keywords:  GDF15; biological circuits; biomarkers; cytokines; disease; energy; exercise; healing; inflammation; mitochondria; oxygen; physical laws; transformation

DOI:  https://doi.org/10.1016/j.cmet.2025.09.002
Brain Commun. 2025 ;7(5): fcaf369

Biallelic NDUFA9 variants cause a progressive neurodevelopmental disorder with prominent dystonia and mitochondrial complex I deficiency.

Francesca Magrinelli, Lucie S Taylor, Sahar Sedighzadeh, Dalila Moualek, Mariasavina Severino, Daniel N Grba, Charlotte L Alston, Michael Champion, Ali Reza Tavasoli, Karine Lascelles, Vykuntaraju K Gowda, Varunvenkat M Srinivasan, Sahand Tehrani Fateh, Mohammad Kordi-Tamandani, Ali Khajeh, Saeedeh Yaghoubi, Natalia Dominik, Meisam Babaei, Mohsen Javadzadeh, Jamileh Rezazadeh Varaghchi, Mohammad Miryounesi, Ehsan Ghayoor Karimiani, Meriem Tazir, Lamia Ali Pacha, Kailash P Bhatia, Robert W Taylor, Henry Houlden, Reza Maroofian.

  Biallelic NDUFA9 variants have hitherto been associated with disease in four individuals. Hence, clinicogenetic features of NDUFA9-related disorder remain largely unexplored. To delineate the pheno-genotypic spectrum of NDUFA9-related disorder, we screened genetic databases worldwide and collected phenotypic data on individuals with biallelic NDUFA9 variants, which were functionally investigated when possible. Eight new and four reported cases were identified. Neurodevelopmental delay followed by motor deterioration and seizures were the most common presenting features. Neurodevelopmental disorder was observed in 90% of cases surviving beyond the age of 4 months. Neurological deterioration always started in the first decade. Among ten affected surviving beyond early infancy, major clinical features included dystonia (100%), feeding difficulties/dysphagia/failure to thrive and pyramidal signs (80%), seizures and muscle weakness/atrophy (70%), and moderate-to-severe intellectual disability (60%). All showed basal ganglia MRI signal alterations, with atrophy (50%) and swelling (25%). Four individuals died by the age of 13 years. In addition to four known variants, we identified five new NDUFA9 variants and pinpointed Arg360 (NP_004993.1) as a mutational hotspot. Protein modelling suggested that variants cause NADH:ubiquinone oxidoreductase subunit A9 (NDUFA9) misfolding and/or disruption of binding interfaces. Loss of fully assembled complex I with decreased steady-state NDUFA9 levels and/or complex I activity was documented in fibroblasts from three affected individuals. Our study strengthens the evidence that biallelic NDUFA9 variants cause mitochondrial complex I deficiency presenting with a broad spectrum of progressive neurodevelopmental disorder, often accompanied by prominent dystonia, and a characteristic Leigh syndrome MRI pattern.

Keywords:  Leigh syndrome; lactic acidosis; mutational hotspot; seizures; spasticity

DOI:  https://doi.org/10.1093/braincomms/fcaf369
Placenta. 2025 Oct 01. pii: S0143-4004(25)00704-0. [Epub ahead of print]171 140-149

Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.

Leena Kadam, Kaylee Chan, Ethan Tawater, Leslie Myatt.

   INTRODUCTION: The placenta is exposed to an altered metabolic environment in obesity and gestational diabetes (GDM) leading to disruption in placental function. Mitochondria are critical for energy production and cellular adaptation to stress. We previously reported reduced trophoblast mitochondrial respiration in GDM. Here we examine changes in mitochondrial structure dynamics, quality and protein homeostasis as well as clearance in male and female placentas of pregnancies complicated by obesity and GDM. As obesity significantly increases the risk for GDM, our goal is to determine the distinct effects of each on placental mitochondria.
METHODS: We collected placental villous tissue following elective cesarean section at term from lean (LN, pre-pregnancy BMI 18.5-24.9), obese (OB, BMI>30) or obese with type A2 GDM women. Expression of proteins involved in mitochondrial biogenesis, structure dynamics, quality control and clearance were assessed by Western blotting. Significant changes between groups were determined in fetal sex-dependent and independent manner.
RESULTS: Only placentas from obese women showed increase in proteins regulating mitochondrial biogenesis (PGC-1α and SIRT1). We report fetal sex-specific changes in mitochondrial fusion but an overall decline in fission in OB and GDM placentas. Both maternal obesity and GDM affected proteins involved in maintaining mitochondrial protein quality and genome stability. This was accompanied by a reduction in mitochondrial complexes, suggesting impaired mitochondrial function. Obesity led to partial activation of mitophagy pathways (e.g., increased PINK1 without PARKIN activation), but GDM placentas failed to mount this response.
DISCUSSION: Obesity and GDM affect placental mitochondria through distinct complex sex-specific mechanisms that may contribute to altered mitochondrial function.

Keywords:  Diabetes; Mitochondria; Obesity; Placenta; Pregnancy

DOI:  https://doi.org/10.1016/j.placenta.2025.09.019
iScience. 2025 Sep 19. 28(9): 113449

Exploring multiorgan mitochondrial dysfunction in the switch toward progressive MASLD in AMLN mice.

Marica Meroni, Erika Paolini, Miriam Longo, Michele Battistin, Daniele Dondossola, Michela Ripolone, Laura Napoli, Ettore Mosca, Stefania Corti, Paola Dongiovanni.

  Hepatic mitochondrial maladaptation features the transition from metabolic dysfunction-associated steatotic liver disease (MASLD) to Steatohepatitis (MASH) up to fibrosis/cirrhosis. However, it is still unexplored whether mitochondrial alterations also affect adipose tissue, muscle and heart during disease progression. C57Bl/6 mice were fed an AMLN diet to recapitulate the human MASLD spectrum. In the liver, TEM depicted a progressive morphologic dysfunction of mitochondria, which appeared swollen in MASH, with disorganized cristae/matrix loss in MASH-fibrosis. The mitophagy pathway was reduced in MASH-fibrosis, thus explaining the accumulation of damaged mitochondria, whereas mitochondrial complexes activities alongside OXPHOS protein levels and ATP production were dampened across the disease in liver, adipose, muscle, and cardiac tissues. Finally, the release of cell-free circulating mitochondrial DNA into the bloodstream reflected tissue mitochondrial impairment. In sum, we demonstrated that alterations in mitochondrial morphology, life cycle, and activity feature all disease stages in the liver but also in other tissues engaged in MASLD evolution.

Keywords:  Biochemistry; Systems biology; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.113449
NPJ Metab Health Dis. 2024 May 27. 2(1): 6

Multifaceted mitochondria in innate immunity.

Eloïse Marques, Robbin Kramer, Dylan G Ryan.

The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.

DOI: https://doi.org/10.1038/s44324-024-00008-3
Cell Death Dis. 2025 Oct 06. 16(1): 693

The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.

Jule Gerlach, Paola Pireddu, Xiaoqun Zhang, Simon Wetzel, Mara Mennuni, Dusanka Milenkovic, Hendrik Nolte, Fernanda da Silva Rodrigues, Niclas Branzell, Ibrahim Kaya, Rodolfo Garcia Villegas, Diana Rubalcava-Gracia, David Alsina, Regina Feederle, Per E Andrén, Thomas Langer, Per Svenningsson, Roberta Filograna.

The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in the genes encoding these proteins have been linked to severe disorders, including Parkinson's disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-body Chchd2 knockout mouse to investigate the in vivo role of CHCHD2 and its protein complex. We show that CHCHD2 is crucial for sustaining full motor capacity, normal striatal dopamine levels, and lipid homeostasis in the brain of adult male mice. We also demonstrate that in mouse tissues, CHCHD2 and CHCHD10 exist exclusively as a high molecular weight complex, whose levels are finely tuned under physiological conditions. In response to mitochondrial dysfunction, the abundance and size of the CHCHD2-CHCHD10 complex increase, a mechanism conserved across different tissues. Although the loss of CHCHD2 does not abolish CHCHD10 oligomerization, it enhances cell vulnerability to mitochondrial stress, suggesting that CHCHD2 is protective against mitochondrial damage. Our findings uncover the role of CHCHD2 in preserving tissue homeostasis and provide important insights into the involvement of the CHCHD2-CHCHD10 complex in human diseases.

DOI: https://doi.org/10.1038/s41419-025-08030-z
Science. 2025 Oct 09. 390(6769): 114-115

First approved drug for mitochondrial disease raises hopes for more.

Mitch Leslie.

Researchers are testing multiple treatments for the rare genetic conditions.

DOI: https://doi.org/10.1126/science.aec9018
Brain Commun. 2025 ;7(5): fcaf342

Outcomes misaligned in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): implications for trial design.

Renae J Stefanetti, Sarah J Charman, Jane Newman, Kate Hallsworth, Alasdair P Blain, Yi Shiau Ng, Gráinne S Gorman.

  The m.3243A>G variant in the MT-TL1 gene is the most prevalent pathogenic variant in mitochondrial DNA in adults, associated with a wide clinical spectrum from asymptomatic individuals to mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. Although pharmacological trials in mitochondrial disorders are increasing, the lack of validated endpoints remains a significant barrier to therapeutic development. This cross-sectional observational study aimed to evaluate patients with and without mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome to identify factors associated with disease burden. Seventeen individuals genetically confirmed to harbour the heteroplasmic m.3243A>G pathogenic variant were enrolled: six who met the consensus-based diagnostic criteria for mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (median age: 30.0 (inter-quartile range: 29.3-45.0) years). Ten patients who did not have a previous history of stroke-like episodes were assigned as 'non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes' (age: 37.5 (32.8-48.3) years). Of these patients in the non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes group, seven exhibited variable features of mitochondrial disease, including hearing loss, diabetes mellitus, migraine and gastrointestinal involvement, while the remaining three were asymptomatic. One patient was excluded from analysis due to a confirmed ischaemic stroke unrelated to mitochondrial disease. Assessments included disease severity (Newcastle mitochondrial disease adult scale) and patient-reported outcomes of fatigue (fatigue impact scale), health-related quality of life (Newcastle Mitochondrial-QoL), mental well-being (Warwick-Edinburgh mental wellbeing scale), autonomic symptoms (the composite autonomic symptom) and physical activity (The International Physical Activity Questionnaire). Performance outcomes included timed-up and go, handgrip strength, cardiopulmonary exercise testing and accelerometry. Age- and sex-matched healthy controls were included for comparison of accelerometry data (age: 35.5 (28.8-50.5) years). Despite comparable age and mitochondrial DNA heteroplasmy, patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome had significantly higher disease burden, reduced exercise capacity and lower levels of objectively measured physical activity compared to non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes and controls (P < 0.05-0.001). Patient-reported outcomes did not significantly differ between mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome/non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. While non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes patients showed expected alignment between perceived and objective measures, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome patients demonstrated weak, absent, or paradoxical associations. This mismatch may reflect altered symptom perception, cognitive impairment, or disease-related adaptation. These findings underscore the complexity of disease expression in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. Regulatory agencies encourage the inclusion of patient-centred endpoints; however, this study highlights the potential limitations of relying solely on patient-reported outcomes. The divergence between subjective and objective assessments supports the need for multi-dimensional outcomes that integrate both patient perspectives and objective measures to enhance the reliability and interpretability of clinical trials in primary mitochondrial disease.

Keywords:  MELAS syndrome; m.3243A>G; mitochondrial; outcome measures; stroke-like episodes

DOI:  https://doi.org/10.1093/braincomms/fcaf342
Nat Commun. 2025 Oct 10. 16(1): 9053

Quantitative cellular characterization of extracellular mitochondria uptake and delivery.

Zahra Al Amir Dache, Maud Chevé, Julia Dancourt, Grégory Lavieu.

Mitochondria are essential intracellular organelles responsible for energy production. Over the past two decades, unconventional intercellular mitochondrial transfer has been reported, but the nature of the transport intermediates, the efficiency of the process, and the cellular mechanisms involved in their uptake and putative integration by acceptor cells remain poorly understood. This gap in knowledge is especially significant given the potential therapeutic applications of mitochondrial transplantation. In this study, we use quantifiable cell biology and biochemical approaches to assess intercellular mitochondria exchange. Our findings suggest that low amount of free mitochondria can be released into conditioned media and subsequently internalized by recipient cells, primarily via fluid-phase uptake, although alternative or concurrent endocytic pathways may also contribute. Notably, we show that a subset of internalized mitochondria escapes the endosomal compartment, reaches the cytosol, and may integrate into the host cell's pre-existing mitochondrial network.

DOI: https://doi.org/10.1038/s41467-025-64147-x
Diabetologia. 2025 Oct 09.

Placental mTOR signalling links mitochondrial dysfunction, nutrient transport and neonatal beta cell perturbations in mice.

Megan Beetch, Eunice Oribamise, Seokwon Jo, Briana Clifton, Sarah Larson, Alex Hausmann, Alicia Wong, Brian Akhaphong, Elizabeth Morgan, Emilyn U Alejandro.

   AIMS/HYPOTHESIS: Fetal programming of metabolic health is influenced by the in utero environment. The placental nutrient sensor mechanistic target of rapamycin (mTOR) is implicated in regulating fetal growth and programming of offspring metabolic health, but the mechanisms are unknown.
METHODS: Using a placental mTOR deficiency model to induce fetal growth restriction (FGR), we investigated mTOR-modulated placental mitochondrial function, nutrient transport and developmental programming of pancreatic beta cells, which are exquisitely sensitive to nutrient levels in utero.
RESULTS: We found defects in placental mitochondria function and morphology that were specific to placentas of mTOR knockout (mTORKO) mice. Despite smaller placentas and FGR in both sexes, nutrient transporter expression and leucine flux were paradoxically increased in female mTORKO placentas. Female fetuses exposed to placental mTOR deficiency (mTORKOpl) displayed significantly reduced circulating insulin without neonatal perturbations in insulin secretion. However, average beta cell size and proliferation were increased in mTORKOpl female fetuses, possibly driven by system A (SNAT) amino acids, suggesting an immature beta cell phenotype. Adult mTORKOpl female offspring exhibit increased susceptibility to diet-induced obesity, insulin resistance and inability to mount a beta cell mass response to a hypernutrient environment.
CONCLUSIONS/INTERPRETATION: Our novel in vivo model of direct placental mTOR-driven FGR provides strong evidence linking placental dysfunction and amino acid transport to proper programming of beta cells in early life.

Keywords:  Amino acid transport; Beta cells; Insulin secretion; Mitochondria; Placenta; mTOR signalling

DOI:  https://doi.org/10.1007/s00125-025-06542-z
Clin Genet. 2025 Oct 11.

Genotype-Phenotype Correlations in Chinese Pediatric Patients With Single Large-Scale Mitochondrial DNA Deletion Disorders.

Jun Wang, Minhan Song, Zhimei Liu, Chaolong Xu, Ying Zou, Xin Duan, Yang Liu, Weihua Zhang, Jiuwei Li, Fang Fang.

  This study investigated clinical and genetic characteristics of Chinese pediatric patients with single large-scale mitochondrial DNA deletions (SLSMD). We analyzed 28 patients (July 2004-March 2025) using long-range PCR and next-generation sequencing. Spearman correlation and ANOVA assessed genotype-phenotype relationships. Patients (mean age 5.52 ± 3.96 years) exhibited multi-organ involvement (5.43 ± 1.87 organs). Common initial presentations included ocular (29%), neurologic, and endocrine dysfunction. Only 14.3% had the classic 4977 bp deletion, and 23 novel deletions were identified in 25 patients. Larger deletions correlated with more deleted MRC complexes (r = 0.516, p = 0.0123) and more deleted tRNAs (r = 0.534, p = 0.0103). Kearns-Sayre syndrome (KSS) patients had later onset (p = 0.0337), larger deletions (p = 0.0263), and greater tRNA/MRC complex (p = 0.0263, p = 0.0319) involvement than non-KSS patients. SLSMD in Chinese children primarily causes KSS, Pearson syndrome (PS), and progressive ophthalmoplegia with multi-organ involvement. Genotype-phenotype correlations exist, particularly between deletion size, onset age, and disease severity. KSS patients show distinct genetic and clinical profiles, suggesting slower progression. This study expands the known SLSMD spectrum and underscores mitochondrial testing in pediatric multi-organ disorders.

Keywords:  KSS; mitochondrial diseases; mtDNA; single large deletions

DOI:  https://doi.org/10.1111/cge.70089
Am J Physiol Endocrinol Metab. 2025 Oct 08.

Markers of mitochondrial function and oxidative metabolism in skeletal muscle do not display intrinsic circadian regulation in female mice.

Liam S Fitzgerald, Connor Scott Reynoso Spurrier, Nathan Lau, Miles Melamed, Lindsey A Burnett, Gretchen A Meyer, Chang Gui, Andrea L Hevener, James A Sanford, Simon Schenk.

  Mitochondria are key regulators of metabolism and ATP supply in skeletal muscle, while circadian rhythms influence many physiological processes. However, whether mitochondrial function is intrinsically regulated in a circadian manner in mouse skeletal muscle is inadequately understood. Accordingly, we measured post-absorptive transcript abundance of markers of mitochondrial autophagy, dynamics, and metabolism (extensor digitorum longus [EDL], soleus, gastrocnemius), protein abundance of electron transport chain complexes (EDL and soleus), enzymatic activity of SDH (tibialis anterior and plantaris), and maximal mitochondrial respiration (tibialis anterior) in different skeletal muscles from female C57BL/6NJ mice at four zeitgeber times: 1, 7, 13, and 19. Our findings demonstrate that markers of mitochondrial function and oxidative metabolism do not display intrinsic time-of-day regulation at the gene, protein, enzymatic, or functional level. The core-clock genes Bmal1 and Dbp exhibited intrinsic circadian rhythmicity in skeletal muscle (i.e., EDL, soleus, gastrocnemius) and circadian amplitude varied by muscle type. These findings demonstrate that female mouse skeletal muscle does not display circadian regulation of markers of mitochondrial function or oxidative metabolism over 24 hours.

Keywords:  chronobiology; extensor digitorum longus; soleus; tibialis anterior; time-of-day

DOI:  https://doi.org/10.1152/ajpendo.00027.2025
Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2508809122

STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.

Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.

  The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the alternate pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet rapid mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process have remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.

Keywords:  cholesterol; intermembrane space; lipoid congenital adrenal hyperplasia; mitochondria; steroidogenesis

DOI:  https://doi.org/10.1073/pnas.2508809122
J Physiol. 2025 Oct 09.

Mitochondrial Ca2+ uniporter haploinsufficiency leads to sexually dimorphic redox imbalance and metabolic remodelling in the mouse brain.

Jenna Gray, Girish Halemirle, Beatriz Ferrán, Hadyn Rose, Traci L Redwine, Sophia Pham, Bo Hagy, Atul Pranay, Jennifer Giorgione, Stacy A Hussong, Veronica Galvan, Kenneth Humphries, Holly Van Remmen, Mike Kinter, William E Sonntag, Pankaj K Singh, Carlos Manlio Díaz-García.

  The mitochondrial Ca2+ uniporter (MCU) links energy metabolism to cell excitability and signalling throughout the lifespan. However, whether neural metabolism responds to MCU impairments in a sex-specific manner has remained unknown, especially in models with partial MCU downregulation. Using hippocampal slices from adult heterozygous Mcu knock-out (hKO) mice, we observed sexually dimorphic changes in NAD(P)H autofluorescence dynamics following neuronal stimulation. In male mice, these signals were preserved despite decreased mitochondrial Ca2+ uptake, likely due to increased MDH2 levels and potentially other enzymes from the tricarboxylic acid cycle, the malate aspartate shuttle, and glycolysis. In contrast to males, neural tissue from female hKO mice showed delayed NAD(P)H production and limited NAD+ availability when compared to sex-matched controls, despite intact mitochondrial Ca2+ uptake. In addition, both male and female hKO mice exhibit decreased NADP+ levels and GSH/GSSG ratios (along with increased protein S-glutathionylation), indicating a weakened antioxidant capacity. Strikingly, markers of oxidative damage were also decreased (albeit more prominently in male mice), suggesting attenuated generation of reactive oxygen species. In addition, sex-specific changes in the hippocampal metabolome were manifested in hKO mice, along with a common decrease in spermidine levels. However, spermidine-dependent hypusination of eIF5A remained unaltered, suggesting further compensatory mechanisms at this age. In summary, our findings indicate that brain tissue can adapt to partial MCU deficits by salvaging most mitochondrial NADH production in active states, while compromising redox signalling and the polyamine pathway. The interplay between these molecular phenotypes likely impacts neurological conditions and potentially cognitive impairment with age. KEY POINTS: The inactivation of one Mcu allele (which encodes the mitochondrial Ca2+ uniporter) leads to altered neuronal excitability and attenuated mitochondrial Ca2+ elevations in active neurons from 6- to 12-months-old female and male mice, respectively. Tissue autofluorescence imaging reveals delayed mitochondrial NAD(P)H production in stimulated hippocampal tissue from female but not male heterozygous Mcu knockout mice. Mitochondrial Ca2+ uniporter haploinsufficiency is characterized by a sex-specific decrease in oxidative stress markers in the brain, despite a decline in NADP+ levels and the GSH/GSSG ratio in both male and female mice. Changes in the abundance of enzymes and polar metabolites in brain tissue reveal sexually dimorphic metabolic remodelling in the context of Mcu haploinsufficiency. Life-long downregulation of the mitochondrial Ca2+ uniporter results in decreased hippocampal spermidine levels in adult male and female mice.

Keywords:  NAD(P)H; brain metabolism; calcium; hippocampus; mitochondria; sexual dimorphism; spermidine

DOI:  https://doi.org/10.1113/JP287618
J Respir Biol Transl Med. 2025 ;2(3):

Mitochondrial Lon Peptidase 1 Controls Diaphragm and Lung Development in a Context-Dependent Manner.

Le Xu, Chunting Tan, Nicole Talaba, Andrew Sou, Yufeng Shen, Wendy K Chung, David J McCulley, Xin Sun.

  Congenital Diaphragmatic Hernia (CDH) is a rare neonatal disorder causing diaphragmatic defects and cardiopulmonary hypoplasia, traditionally attributed to mechanical compression from organ herniation. However, emerging evidence suggests genetic mutations may independently impair lung development, prompting debate over CDH etiology. Here, we investigated the requirement of mitochondrial function guarded by LON peptidase 1 (Lonp1), a CDH risk gene, in either diaphragm or lung development. Lonp1 loss in skeletal muscles of the diaphragm led to its thinning and membranization, recapitulating the pathology of sac-type CDH. On the other hand, lung-specific inactivation caused severe hypoplasia with defective branching morphogenesis, independent of diaphragm anomalies. Molecularly, Lonp1 disruption dysregulated key transcription factors and signaling pathways known to be critical for early lung development. Our findings here revealed that mitochondrial defects contribute to the pathogenesis of CDH in an organ and cell type specific manner, opening new avenues for drug and therapeutic development.

Keywords:  CDH; Diaphragm; FGF10; LONP1; Lung; Mitochondria; SHH

DOI:  https://doi.org/10.70322/jrbtm.2025.10008
Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2519902122

Activity-dependent citrate dynamics in neurons.

Paul C Rosen, Panhui Fu, Beatriz Ferrán, Erica Kim, Daniel J Brooks, Daniel C Lim, Carlos Manlio Díaz-García, Gary Yellen.

  Glycolytic enzymes sense metabolite levels to adapt rapidly to changing energy demands, but measuring the levels of these effectors with spatiotemporal precision in live cells has been challenging. We addressed this question in the context of neuronal depolarization, which activates glycolysis, focusing on the glycolysis inhibitor citrate. We engineered a pair of quantitative fluorescent biosensors for citrate that address several limitations (affinity, pH, Mg2+, and temperature) of existing citrate biosensors. Using two-photon fluorescence lifetime imaging, we found that free citrate in the cytosol of neurons in acute mouse brain slices declines two-to-threefold within seconds of neuronal activation and then returns to baseline over a few minutes. The stimulation-dependent citrate transient depends at least in part on the mitochondrial calcium uniporter. These types of live metabolite measurements are essential for achieving a nuanced understanding of the fast control of glycolysis.

Keywords:  fluorescence lifetime; genetically encoded fluorescent biosensor; glycolytic regulation; mitochondrial calcium uniporter

DOI:  https://doi.org/10.1073/pnas.2519902122
Neurosci Lett. 2025 Oct 06. pii: S0304-3940(25)00299-X. [Epub ahead of print]868 138410

Mitochondrial dysfunction and aging can be alleviated by modulating calcineurin and cardiolipin dynamics following stroke.

Pallab Bhattacharya, Shailendra Saraf, Anirban Barik, Bijoyani Ghosh, Aishika Datta, Davendra Singh Malik.

  The crucial influence of mitochondria in ischemic stroke pathophysiology presents many unexplored yet promising avenues for therapeutic strategies and clinical outcomes. Post-stroke mitochondrial dysfunction contributes to aggravated levels of calcium overload and apoptosis. This dysfunction is signified by disruption of the mitochondrial lipids such as cardiolipin, along with mitochondrial DNA mutation, leading to an imbalance in mitophagy. Calcium overload-mediated calcineurin overexpression has been reported to exacerbate mitochondrial damage and further contribute to neuronal apoptosis. In our study, we explored the alterations in the mitochondrial function following inhibition of the calcium-mediated calcineurin levels in post-stroke condition. In a rodent model of middle cerebral artery occlusion (MCAo), we observed that the inhibition of the calcium channels in post-stroke condition led to restored neuronal histology and viability following upregulation of the antioxidant levels. At the mitochondrial level, calcium channel inhibition downregulated calcineurin activation and normalized cardiolipin concentration, mitochondrial membrane potential, and respiratory control ratio in post-stroke condition. This inhibition also balanced the mitochondrial dynamics proteins and mitophagy towards neuronal recovery following ischemic stress. Moreover, it also normalized the expression of TERT, a key marker of mitochondrial health and aging. These findings highlight the role of calcium-mediated calcineurin in influencing mitochondrial dysfunction and aging in ischemic stroke. Thus, calcium channel inhibition offers a promising therapeutic strategy by preserving mitochondrial integrity and promoting neuroprotection following stroke.

Keywords:  Calcineurin; Calcium signaling; Cardiolipin; Mitochondrial aging; Stroke

DOI:  https://doi.org/10.1016/j.neulet.2025.138410
Front Cell Neurosci. 2025 ;19 1636185

Spatiotemporal crosstalk among mitochondrial dynamics, NLRP3 inflammasome activation, and histone lactylation drives α-synuclein pathology in prodromal Parkinson's disease.

Peizhu Lv, Xia Chen, Shiping Liu, Yu Zhang, Yan Bai, Shun Wang, Yulin Wang.

  This article conducts a systematic search of literature in the fields of neuroscience, cell biology, immunometabolism, etc. from 1990 to 2025, with PubMed/WebofScience as the core database. Experimental and clinical studies covering the core mechanisms of the preprophase of PD (mitochondrial imbalance → NLRP3 activation → lactation modification → α -SYN pathology) were included, and non-interaction mechanisms and clinical-phase studies were excluded. The pathological interaction network of mitochondrial dynamic imbalance, lysosomes - mitochondrial interaction disorder and neuroinflammation in Parkinson's disease (PD) was explained. Construct a three-dimensional pathological network of "energy-inflammation-protein homeostasis" to provide a theoretical basis for early intervention. The imbalance of mitochondrial fission/fusion leads to the accumulation of fragmented mitochondria, triggering energy metabolism disorders and oxidative stress; abnormal aggregation of α-synuclein (α-syn) disrupts mitochondrial-endoplasmic reticulum membrane (MAM) calcium signaling, upregulates Miro protein to inhibit mitochondrial autophagy clearance, forming a vicious cycle of neuronal damage. Defects in the PINK1/Parkin pathway and LRRK2 mutations interfere with the turnover of mitochondrial fission complexes, causing mtDNA leakage, activating the NLRP3 inflammasome, and driving neuroinflammatory cascades. Additionally, lysosomal dysfunction caused by GBA1 mutations exacerbates mitochondrial quality control defects through Rab7 activity imbalance. Abnormal lactate metabolism may influence inflammasome activity through epigenetic regulation, but its role in PD needs further validation. Based on the above mechanisms, a diagnostic strategy for the prodromal phase integrating dynamic monitoring of mitochondrial fragmentation index, lysosomal function markers, and inflammatory factors is proposed, along with new intervention directions targeting Drp1, NLRP3, and the lysosome-mitochondria interface.

Keywords:  NLRP3 inflammasome; Parkinson’s disease; lactylation modification; mitochondrial dynamics; prodromal phase

DOI:  https://doi.org/10.3389/fncel.2025.1636185
BMC Pregnancy Childbirth. 2025 Oct 10. 25(1): 1062

Distinct maternal DNA methylation associations with gestational age at early and late-mid term pregnancy in a low- and middle-income country: evaluation of biological, genetic, and psychosocial contributors.

Maternal-infant Global Health Team (MiGHT) – Collaborators in Research

  Mothers undergo physiological and molecular changes over the course of gestation. These modifications "get under the skin" and may be reflected in the maternal epigenome through processes such as DNA methylation. Such an epigenetic mark may offer insights into maternal responses to prenatal influences and biological cues from the developing fetus, thereby functioning as an indirect indicator of the conditions the fetus experiences in utero. We measured whole blood DNA methylation using the MethylationEPIC BeadChip Infinium microarray v1.0 in 22 pregnant women from Pakistan, a low- and middle-income country (LMIC), at two timepoints during their term pregnancies (early: 10-19 weeks and late-mid: 22-29 weeks). We used DNA methylation profiles to predict immune cell proportions and tested differences in these proportions and DNA methylation patterns between the two timepoints. Further, we evaluated DNA methylation associations with gestational age at each timepoint and examined the contribution of genetic, psychosocial, and biological factors. Our analyses documented changes in immune cell proportions and DNA methylation profiles over the course of gestation, albeit in a small percentage of the measured DNA methylome. We also observed timepoint-specific DNA methylation associations with gestational age, predominantly at early pregnancy, with predicted interleukin-6 level and socioeconomic status contributing to a few of these associations. On comparing to three external cohorts from different sociocultural contexts, we also noted these signatures to be unique to LMIC settings. Overall, these changes measured in term pregnancies may be used to assess both fluctuations in pregnancy and birth outcomes, particular in women from LMIC settings.

Keywords:  DNA methylation; Fetal environment; Gestational age at birth; Immune cell types; LMIC; Maternal blood; MiGHT; Pregnancy

DOI:  https://doi.org/10.1186/s12884-025-08037-6
Front Neuroendocrinol. 2025 Oct 03. pii: S0091-3022(25)00043-3. [Epub ahead of print] 101217

Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.

George B Stefano, Pascal Büttiker, Simon Weissenberger, Jiri Raboch, Martin Anders.

  While mitochondria provide critical energy resources, mitochondrial dysfunction can lead to both metabolic and neurodegenerative disorders. Primary mitochondrial disorders (e.g., Leigh syndrome) are uniformly associated with profound neurodegeneration. Recent studies have also implicated mitochondrial dysfunction as a central feature of progressive neurodegenerative diseases, notably Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease. In addition to its profound impact on metabolic disease, the glucagon-like peptide-1 receptor agonist, semaglutide, has significant neuroprotective features and may limit the progression of one or more of these disorders. These observations might be explained at least in part by the impact of this drug on mitochondrial function and energy production. Collectively, these observations highlight disrupted energy homeostasis as a critical feature of neurodegenerative disease and suggest novel targets for the development of much-needed new neuropharmaceutical strategies.

Keywords:  Alzheimer’s disease; Glucagon-like Peptide 1; Mitochondria; Neurodegenerative disease; Oxidative phosphorylation; Parkinson’s disease; Semaglutide

DOI:  https://doi.org/10.1016/j.yfrne.2025.101217
Nat Aging. 2025 Oct 08.

The secreted metabolite sensor CtBP2 links metabolism to healthy lifespan.

Motohiro Sekiya, Kenta Kainoh, Wanpei Chen, Daichi Yamazaki, Tomomi Tsuyuzaki, Yuto Kobari, Ayumi Nakata, Kenji Saito, Nao Aono-Soma, Ali Majid, Hiroshi Ohno, Takafumi Miyamoto, Takashi Matsuzaka, Rikako Nakajima, Takaaki Matsuda, Yuki Murayama, Yoko Sugano, Yoshinori Osaki, Hitoshi Iwasaki, Hitoshi Shimano.

Within each cell, metabolite-sensing factors respond to coordinate metabolic homeostasis. How metabolic homeostasis is regulated intercellularly and how this may become dysregulated with age, however, remains underexplored. Here we describe a system regulated by a metabolite sensor, CtBP2. CtBP2 is secreted via exosomes in response to reductive metabolism, which is suppressed by oxidative stress. Exosomal CtBP2 administration extends lifespan in aged mice and improves healthspan in particular by reducing frailty. Mechanistically, we identify activation of CYB5R3 and AMPK downstream of exosomal CtBP2. Consistently, serum CtBP2 levels decrease with age and are negatively associated with cardiovascular disease incidence in humans yet are elevated in individuals from families with a history of longevity. Together our findings define a CtBP2-mediated metabolic system with potential for future clinical applications.

DOI: https://doi.org/10.1038/s43587-025-00973-4