bims-mitmed 2025-11-16 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–11–16
24 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy.
Alterations in peroxisome-mitochondria interplay in skeletal muscle accelerate muscle dysfunction.
Liver Involvement in POLG Disease-a Multicentre Cohort Study of 202 Patients.
The genotypic and phenotypic landscape of PDHA1-related pyruvate dehydrogenase complex deficiency.
Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.
Characterization of Novel POLG Mutations in Mitochondrial Encephalomyopathy: Pathogenic Validation and Comprehensive Genetic Profiling.
Myosin-19 and Miro Regulate Mitochondria-Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture.
Alternative start codon selection shapes mitochondrial function and rare human diseases.
MT-ATP6 variant as a cause of adult-onset hereditary spastic paraparesis: A case report and literature review.
Advances and challenges in modeling Charcot-Marie-Tooth type 2A using iPSC-derived models.
Developmental Differences in Myocardial Mitochondrial Reticulum Networks in the Offspring Exposed to Diabetic Pregnancy.
Developmental bioenergetics: a comparative perspective on mitochondrial efficiency in paediatric physiology.
From Mitochondria to Immunity: The Emerging Roles of Mitochondria-Derived Vesicles and Small Extracellular Vesicles in Cellular Communication and Disease.
STX4 Is Indispensable for Mitochondrial Homeostasis in Skeletal Muscle.
Mitochondria-Mediated Mechanisms of Ferroptosis in Neurological Diseases.
Perioperative Care of a Child With Combined Oxidative Phosphorylation Deficiency 6: Total Intravenous Anesthesia With Remimazolam.
Intravenous mitochondrial transplantation as an adjunctive therapy for dilated cardiomyopathy.
Development of Cellular Energy Metabolism During Differentiation of Human iPSCs into Cortical Neurons.
Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition.
Intrinsic dysfunction in muscle stem cells lacking dystrophin begins during secondary myogenesis.
CHCHD2 mutant mice link mitochondrial deficits to PD pathophysiology.
Longitudinal Ultrasound Imaging of an Individual Fetus In Utero Using an Echogenic Marker.

Sci Adv. 2025 Nov 14. 11(46): eaea4660

The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.

Laura S Kremer, Zoe Golder, Tom Barton-Owen, Polyxeni Papadea, Camilla Koolmeister, Patrick F Chinnery, Nils-Göran Larsson.

Mammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.

DOI: https://doi.org/10.1126/sciadv.aea4660
Autophagy. 2025 Nov 13.

Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.

Tian Lan, Dantong Shang, Lan Lin, Haoyu Wang, Juan Zou, Mengxin Hu, Hanhua Cheng, Rongjia Zhou.

  Mitochondrial nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, yet its roles and mechanisms in mitophagy and innate immunity remain poorly understood. In this study, we identify mitochondrial NAD+ depletion that causes mitophagy dysfunction and inflammation. We find that depletion of mitochondrial NAD+ owing to deficiency of the mitochondrial NAD+ transporter SLC25A51 impairs BNIP3-mediated mitophagy. Loss of mitochondrial NAD+ inhibits SIRT3-mediated deacetylation of FOXO3, leading to transcriptional downregulation of BNIP3 and subsequent disruption of MAP1LC3B/LC3B recruitment. Notably, mitochondrial NAD+ depletion promotes mitochondrial DNA (mtDNA) release from mitochondria to the cytosol upon oxidative stress, thereby exacerbating the type I interferon response to free cytosolic mtDNA via activation of the CGAS-STING1 signaling pathway. Our findings reveal a novel mechanistic link among mitochondrial NAD+, mitophagy, and mtDNA-induced inflammation by genetic manipulation of cell lines, highlighting mitochondrial NAD+ as a potential therapeutic target for mitigating sterile inflammation triggered by free cytosolic mtDNA. Thus, the study provides new insights into the crosstalk among mitochondrial homeostasis, inflammation, and innate immunity.

Keywords:  Cytosolic mtDNA; SLC25A51; inflammation; innate immunity; mitochondrial NAD+; mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2589909
Brain. 2025 Nov 14. pii: awaf422. [Epub ahead of print]

Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy.

Claudio Fiorini, Neringa Jurkute, Alessandra Torraco, Chiara La Morgia, Daniele Ghezzi, Gaia Tioli, Laura Rigobello, Danara Ormanbekova, Alessandro Berghella, Alberto Pietro Pasti, Flavia Palombo, Piero Barboni, Maria Lucia Cascavilla, Federico Sadun, Annamaria De Negri, Enrico Bertini, Olimpia Musumeci, Anna Ardissone, Teresa Rizza, Giancarlo Iarossi, Gabriella Silvestri, Salvatore Rossi, Anastasia Altobelli, Antony T Moore, Thomas Cullup, Andrew R Webster, Indran Davagnanam, Michel Michaelides, Samantha Malka, Hana Ptackova, Hana Stufkova, Marketa Tesarova, Petra Liskova, Leopold Zeng, Thomas Klopstock, Robert Kopajtich, Christiane Neuhofer, Holger Prokisch, Costanza Lamperti, Alfredo A Sadun, Patrick Yu-Wai-Man, Valerio Carelli, Francesco Musiani, Luisa Iommarini, Rosalba Carrozzo, Gavin Arno, Leonardo Caporali.

Our understanding of the genetic landscape of inherited optic neuropathies has grown significantly over the past decades, and it is now known to involve many genes found in both the nuclear and mitochondrial genomes, exhibiting all possible inheritance patterns. Furthermore, pathogenic variants in nuclear genes of mitochondrial respiratory Complex I (CI) subunits have been identified in some cases of ION, in addition to the more common severe presentation of CI deficiencies, usually with early onset. We conducted NGS screening of CI genes to identify potential causative variants in patients with optic atrophy, also performing comprehensive clinical assessments, including neuroimaging studies (MRI) and neurological evaluations. Detailed molecular structure modeling was performed to better evaluate the damaging effects of both novel and previously reported variants in the relevant CI subunits. We identified and characterized candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear CI-related genes encoding polypeptides involved in the structure of CI, including 3 core subunits (NDUFS7, NDUFV1, NDUFV2), 4 accessory subunits (NDUFA1, NDUFA10, NDUFA12, NDUFB11), and 4 assembly factors (NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF8). Notably, defects in core CI subunits in this cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defects. Our case series broadens the genetic spectrum of inherited optic neuropathies, emphasizing the crucial role of nuclear CI genes in its pathogenesis. The arLHON phenotype emerges as linked to numerous nuclear CI genes for which an insidious onset of optic atrophy is also reported, and in some cases the same variant may underlie both phenotypes. Overall, we highlight the possibly so far underestimated prevalence of CI nuclear subunits in the molecular diagnosis of ION, prompting to include all CI-related genes in the standard diagnostic screening.

DOI: https://doi.org/10.1093/brain/awaf422
Nat Commun. 2025 Nov 10. 16(1): 9868

Alterations in peroxisome-mitochondria interplay in skeletal muscle accelerate muscle dysfunction.

Marco Scalabrin, Eloisa Turco, Ilaria Davigo, Riccardo Filadi, Leonardo Nogara, Gaia Gherardi, Lucia Barazzuol, Andrea Armani, Giulia Trani, Samuele Negro, Anais Franco-Romero, Yorrick Jaspers, Elisa Baschiera, Rossella De Cegli, Eugenio Del Prete, Tito Cali, Bert Blaauw, Leonardo Salviati, Michela Rigoni, Cristina Mammucari, Sylvie Caspar-Bauguil, Cedric Moro, Paola Pizzo, Marco Sandri, Stephan Kemp, Vanina Romanello.

Skeletal muscles, which constitute 40-50% of body mass, regulate whole-body energy expenditure and glucose and lipid metabolism. Peroxisomes are dynamic organelles that play a crucial role in lipid metabolism and clearance of reactive oxygen species, however their role in skeletal muscle remains poorly understood. To clarify this issue, we generated a muscle-specific transgenic mouse line with peroxisome import deficiency through the deletion of peroxisomal biogenesis factor 5 (Pex5). Here, we show that Pex5 inhibition results in impaired lipid metabolism, reduced muscle force and exercise performance. Moreover, mitochondrial structure, content, and function are also altered, accelerating the onset of age-related structural defects, neuromuscular junction degeneration, and muscle atrophy. Consistent with these observations, we observe a decline in peroxisomal content in the muscles of control mice undergoing natural aging. Altogether, our findings show the importance of preserving peroxisomal function and their interplay with mitochondria to maintain muscle health during aging.

DOI: https://doi.org/10.1038/s41467-025-64833-w
J Inherit Metab Dis. 2025 Nov;48(6): e70112

Liver Involvement in POLG Disease-a Multicentre Cohort Study of 202 Patients.

Erle Kristensen, Karin Naess, Martin Engvall, Claus Klingenberg, Magnhild Rasmussen, Eylert Brodtkorb, Elsebet Ostergaard, Irenaeus de Coo, Leticia Pias-Peleteiro, Pirjo Isohanni, Johanna Uusimaa, Kari Majamaa, Mikko Kärppä, Mika H Martikainen, Juan Dario Ortigoza-Escobar, Trine Tangeraas, Siren Berland, Carolyn M Sue, Judith Sylvia Walker, Emma Harrison, Heather Biggs, Rita Horvath, Niklas Darin, Shamima Rahman, Omar Hikmat.

  Liver involvement in POLG disease is common and associated with high morbidity and mortality. Detailed, large-scale, systematic studies of liver involvement are lacking. This study aims to describe the onset, clinical course and prognostic implications of liver involvement in POLG disease. We conducted a multinational, retrospective study including clinical, genetic and biochemical data from patients with confirmed POLG disease. Patients were stratified according to age of disease onset: early-onset (< 12 years), juvenile/adult-onset (12-40 years), and late-onset (> 40 years). Of the 202 patients, 110 (54%) had liver involvement. This could present at any time during the lifespan, but occurred more frequently in patients with early-onset disease (76/98, 78%). Median onset age for liver involvement in females was 7 years (range: 1 month to 50 years), and 21 months in males (birth to 71 years). Infection-triggered disease onset carried a significantly higher risk of liver involvement than spontaneous or other disease triggers. Eighty-five percent of those with liver involvement also had epilepsy. Liver involvement was an indicator of poor prognosis and was significantly associated with worse survival. This study provides a comprehensive description of liver involvement in a large cohort of POLG disease patients. Liver involvement is common in this disease and associated with significantly worse survival. POLG disease should be considered in children presenting with liver involvement, and rapid genetic testing may guide management decisions. Our findings emphasize the need for early vigilance in monitoring liver involvement in all patients with confirmed POLG disease, particularly those with early-onset disease and during intercurrent infection.

Keywords:  hepatopathy; liver disease; liver transplantation; mitochondrial disorder; mitochondriopathy; valproate

DOI:  https://doi.org/10.1002/jimd.70112
Brain. 2025 Nov 14. pii: awaf430. [Epub ahead of print]

The genotypic and phenotypic landscape of PDHA1-related pyruvate dehydrogenase complex deficiency.

Kajus Merkevicius, Dmitrii Smirnov, Lea D Schlieben, Rebecca Ganetzky, René G Feichtinger, Huafang Jiang, Fang Fang, Tomohiro Ebihara, Kei Murayama, Giulia Ferrera, Anna Ardissone, Dariusz Rokicki, Dorota Wesol-Kucharska, Sabine Schröder, Peter Bauer, Aida Bertoli-Avella, Elsebeth Østergaard, Peter Freisinger, Mirian C H Janssen, Matias Wagner, Omar Abouyousef, Bader Alhaddad, Lama AlAbdi, Fowzan Alkuraya, Charlotte L Alston, Anna Baghdasaryan, Diana Barca, Ivo Barić, Marcello Bellusci, Andrea Bevot, Eugen Boltshauser, Ingo Borggraefe, Juliette Bouchereau, Claudio Bruno, Birute Burnyte, Amy Calhoun, Kari Casas, Mahmut Coker, Ellen Crushell, Pascal De Lonlay, Carlo Dionisi-Vici, Felix Distelmaier, Marni J Falk, Ana Cristina Ferreira, Carlos R Ferreira, Can Ficicioglu, Gulden Fatma Gokçay, Johannes Häberle, Oliver Heath, Albrecht Hellenschmidt, Julia Hoefele, Georg F Hoffmann, Tomas Honzik, Martina Huemer, Patrícia Janeiro, Amel Karaa, Çiğdem Seher Kasapkara, Ilse Kern, Joerg Klepper, Thomas Klopstock, Ina Knerr, Johannes Koch, Zita Krumina, Costanza Lamperti, Elise Lebigot, Zhimei Liu, Esther M Maier, Diego Martinelli, Robert McFarland, Bryce Mendelsohn, Maria Judits Molnar, Helen Mundy, Marie-Cecile Nassogne, Anabela Oliveira, Katrin Õunap, Chiara Panicucci, Sumit Parikh, Heidi Peters, Samia Pichard, Barbara Plecko, Danijela P Ramadža, Gabriela M Repetto, Isabel Rivera, Richard J Rodenburg, Alessandro Rossi, Manuel Schiff, Kathrin Seidemann, Wendy E Smith, Sérgia Soares, Barbara Siri, Katja Steinbrucker, Pasquale Striano, Jolanta Sykut-Cegielska, Galit Tal, Robert W Taylor, Kostas Tsiakas, Sema Kalkan Ucar, Eva Hoytema van Konijnenburg, Mathias Woidy, Joy Yaplito-Lee, Yilmaz Yildiz, Martin Zenker, Petra Zsidegh, Dominik Westphal, Wolfgang Sperl, Thomas Meitinger, Garry K Brown, Holger Prokisch, Johannes A Mayr, Saskia B Wortmann.

  This retrospective study on X-linked PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency combined a systematic literature review with a multicenter survey exploring genotypes, phenotypes, and survival. Data from 891 individuals (45% unpublished) were included. Of note, 53% of cases were females. Median age at last assessment was six years (range 0-80 years, n = 622). We detected 331 different (118 unpublished) PDHA1 variants of which 75% (305/405) had occurred de novo. Variants in this study were uploaded to ClinVar (SCV006297015 - SCV006297345). The 10 most frequent variants accounted for 36% of the diagnoses. Sixty-nine percent of the variants were private; missense (50%) and frameshift (20%) variants were most common. Frameshift/nonsense (FS/N) variants in males (44/401, 11%) were confined to regions escaping nonsense-mediated decay (NMD) and were significantly less frequent than in females (151/461, 33%). Neonatal or infantile (405/529, 77%) presentations were most frequent, with pre/perinatal abnormalities reported in 47% (159/342). FS/N variants in NMD-predicted region 3.9 (95% Confidence Interval (CI) 1.54-11.04) times increased the odds of fetal findings. Females presented significantly earlier (2 months, interquartile range (IQR) 7.0, n = 224) than males (8 months, IQR 16.6, n = 233), with increased risk of neonatal presentation (odds ratio (OR) 3.01 (95% CI 1.279-7.616) when harboring FS/N variants in NMD-predicted region. The overall (n = 242) mean survival time was 10.9 (95% CI 9.9-11.9) years. On average, females survived 4.5 (95% CI 2.62-6.40) years longer than males despite presenting more severe phenotypes. Poor survival was associated with male sex (hazard ratio (HR) 3.3 (95% CI 1.95-5.62)), neonatal presentation (HR 5.5 (95% CI 2.17-14.09)), FS/N variants in NMD-predicted region (HR 4.0 (95% CI 1.78, 9.16)), and splice variants (HR 2.3 (95% CI 1.15, 4.59)). More severe clinical phenotypes were predicted by neonatal or infantile presentations and by female sex. Developmental delay (DD), intellectual disability (ID), muscle hypotonia, abnormal movements, seizures, feeding difficulties, and microcephaly were the most frequent phenotypes, all occurring in more than half. Corpus callosum or basal ganglia alterations and cerebral atrophy were common. Four percent (36/891) were reported to have mild phenotypes with no DD nor ID (25/36 males). This is the largest dataset on a nuclear-encoded defect of mitochondrial energy metabolism. The genotypic and phenotypic details further defines disease landscape and can be used for variant interpretation. The correlations between genotypes, sex, phenotypes and survival, adds a substantial improvement to counselling.

Keywords:  genotype-phenotype correlation; inborn errors of metabolism; inborn metabolic disease; ketogenic diet; mitochondrial disease; treatment

DOI:  https://doi.org/10.1093/brain/awaf430
Int J Mol Sci. 2025 Oct 30. pii: 10581. [Epub ahead of print]26(21):

Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.

Margherita Zamberlan, Martina Semenzato.

  Tunneling nanotubes (TNTs) are dynamic, actin-based intercellular structures that facilitate the transfer of organelles, including mitochondria, between cells. Unlike other protrusive structures such as filopodia and cytonemes, TNTs exhibit structural heterogeneity and functional versatility, enabling both short- and long-range cargo transport. This review explores the mechanisms underlying mitochondrial transfer via TNTs, with a particular focus on cytoskeletal dynamics and the role of key regulatory proteins such as Miro1, GFAP, MICAL2PV, CD38, Connexin 43, M-Sec, thymosin β4, and Talin 2. Miro1 emerges as a central mediator of mitochondrial trafficking, linking organelle motility to cellular stress responses and tissue repair. We delve into the translational implications of TNTs-mediated mitochondrial exchange in regenerative medicine and oncology, highlighting its potential to restore bioenergetics, mitigate oxidative stress, and reprogram cellular states. Despite growing interest, critical gaps remain in understanding the molecular determinants of TNT formation, the quality and fate of transferred mitochondria, and the optimal sources for mitochondrial isolation. Addressing these questions will be essential for harnessing TNTs and mitochondrial transplantation as therapeutic tools.

Keywords:  Miro1; mitochondria; mitochondrial transplantation; tunneling nanotubes

DOI:  https://doi.org/10.3390/ijms262110581
Brain Behav. 2025 Nov;15(11): e71045

Characterization of Novel POLG Mutations in Mitochondrial Encephalomyopathy: Pathogenic Validation and Comprehensive Genetic Profiling.

Fanjing Zhou, Jiang Chen, Tingzheng Zhang, Fengnan Niu, Jinglong Hu, Yun Xu, Meijuan Zhang.

   INTRODUCTION/AIMS: Mitochondrial encephalomyopathies are multisystem disorders caused by defects in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) syndrome is a rare manifestation, often associated with POLG mutations. This study identifies a novel POLG mutation in a SANDO patient, validates its pathogenicity, and analyzes the molecular genetics of 61 reported POLG-SANDO cases.
METHODS: After obtaining informed consent, the proband underwent neurological examination, electromyography, muscle/nerve biopsies (histochemical/ultrastructural analyses), and genetic testing (whole-exome sequencing, mtDNA analysis). Pathogenicity of identified POLG variants was assessed in Cas9-mediated primary neuronal models expressing mutant proteins by measuring reactive oxygen species (ROS) levels and mtDNA copy number (qRT-PCR, ND1/APP ratio). Literature searches (PubMed, CNKI, Wanfang, and ClinVar) identified reported POLG mutations and clinical features in SANDO.
RESULTS: Clinical and biopsy findings confirmed SANDO syndrome. Genetic analysis revealed compound heterozygous POLG mutations: a novel c.3297G>C (p.W1099C) and a known c.1774C>T (p.L592F). Neurons expressing either mutant exhibited elevated ROS levels (p < 0.05) and reduced mtDNA copy number compared with controls. Literature synthesis identified over 30 SANDO-associated POLG mutations, with p.A467T (31.2%) and p.W748S (22.1%) being the most frequent. The mean age of onset was 31.6 years.
CONCLUSIONS: We identify a novel pathogenic POLG variant (p.W1099C) causing mitochondrial dysfunction via impaired mtDNA maintenance, expanding the SANDO genetic spectrum. Functional studies confirmed both mutations induce mitochondrial dysfunction (elevated ROS and decreased mtDNA Copy Number), validating their pathogenicity. The compiled mutation profile aids diagnosis of this phenotypically heterogeneous, frequently misdiagnosed disorder.

Keywords:  POLG mutation; SANDO; mitochondrial encephalomyopathy

DOI:  https://doi.org/10.1002/brb3.71045
Cells. 2025 Oct 23. pii: 1657. [Epub ahead of print]14(21):

Myosin-19 and Miro Regulate Mitochondria-Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture.

Aya Attia, Katarzyna Majstrowicz, Samruddhi Shembekar, Ulrike Honnert, Petra Nikolaus, Birgit Lohmann, Martin Bähler.

  Mitochondrial dynamics are important for cellular health and include morphology, fusion, fission, vesicle formation, transport and contact formation with other organelles. Myosin XIX (Myo19) is an actin-based motor, which competes with TRAK1/2 adaptors of microtubule-based motors for binding to the outer mitochondrial membrane receptors Mitochondrial Rho GTPases 1/2 (Miro). Currently, it is poorly understood how Myo19 contributes to mitochondrial dynamics. Here, we report on a Myo19-deficient mouse model and the ultrastructure of the mitochondria from cells of Myo19-deficient mice and HEK cells, Miro-deficient HEK cells and TRAK1-deficient HAP1 cells. Myo19-deficient mitochondria in MEFs and HEK cells have morphological alterations in the inner mitochondrial membrane with reduced numbers of malformed cristae. In addition, mitochondria in Myo19-deficient cells showed fewer ER-mitochondria contact sites (ERMCSs). In accordance with the ultrastructural observations, Myo19-deficient MEFs had lower oxygen consumption rates and a reduced abundance of OXPHOS supercomplexes. The simultaneous loss of Miro1 and Miro 2 led to a comparable mitochondria phenotype and reduced ERMCSs as observed upon the loss of Myo19. However, the loss of TRAK1 caused only a reduction in the number of cristae, but not ERMCSs. These results demonstrate that both actin- and microtubule-based motors regulate cristae formation, but only Myo19 and its membrane receptor Miro regulate ERMCSs.

Keywords:  Miro1/2; Myosin 19; OXPHOS; TRAK; cristae; mitochondria; outer mitochondrial membrane

DOI:  https://doi.org/10.3390/cells14211657
Mol Cell. 2025 Nov 07. pii: S1097-2765(25)00854-8. [Epub ahead of print]

Alternative start codon selection shapes mitochondrial function and rare human diseases.

Jimmy Ly, Matteo Di Bernardo, Yi Fei Tao, Ekaterina Khalizeva, Christopher J Giuliano, Sebastian Lourido, Mark D Fleming, Iain M Cheeseman.

  Rare genetic diseases collectively affect millions of individuals. A common target of many rare diseases is the mitochondria, intracellular organelles that originated through endosymbiosis. Eukaryotic cells require related proteins to function both within the mitochondria and in the host cell. By analyzing N-terminal protein isoforms generated through alternative start codon selection, we identify hundreds of differentially localized isoform pairs, including dual-localized isoforms that are essential for both mitochondrial and host cell function. Subsets of dual mitochondria-localized isoforms emerged during early eukaryotic evolution, coinciding with mitochondrial endosymbiosis. Importantly, we identify dozens of rare disease alleles that affect these alternative protein variants with unique molecular and clinical consequences. Alternative start codon selection can bypass pathogenic nonsense and frameshift mutations, thereby selectively eliminating specific isoforms, which we term isoform-selective alleles (ISAs). Together, our findings illuminate the evolutionary and pathological relevance of alternative translation, offering insights into the molecular basis of rare human diseases.

Keywords:  TRNT1; alternative N-terminal isoforms; alternative translation; mitochondria; proteomic diversity; rare diseases; start codon selection; translation initiation

DOI:  https://doi.org/10.1016/j.molcel.2025.10.013
J Neuromuscul Dis. 2025 Nov 12. 22143602251391068

MT-ATP6 variant as a cause of adult-onset hereditary spastic paraparesis: A case report and literature review.

Care4Rare Canada Consortium

  BackgroundHereditary spastic paraplegia (HSP) is a heterogenous group of rare genetic disorders characterized by progressive corticospinal and dorsal spinal cord axonal degeneration manifesting as muscle weakness and spasticity of the lower extremities. Over 98% of solved HSP cases are caused by pathogenic variants in the nuclear DNA.CaseWe report a family carrying the m.9035T > C [p.(Leu170Pro)] pathogenic variant in the mitochondrial MT-ATP6 gene in the setting of maternally inherited, late-onset HSP. The proband (age 67 years) presented with classical, late-onset, pure HSP. Her affected daughter (age 39 years) developed late-onset, complex HSP, with asymmetrical axonal sensorimotor polyneuropathy. Her second daughter (age 46 years) carried the same pathogenic variant with high heteroplasmy but was clinically unaffected at last assessment, suggesting age-dependent or incomplete penetrance.Summary of literatureThe substitution of a leucine for a proline affects a highly conserved transmembrane helix of the subunit "a" at a key functional domain in the mitochondrial ATP synthase complex. The m.9035T > C variant has been reported in several families presenting with common phenotypic presentations of ATP6-related disorders such as maternally inherited Leigh syndrome (MILS) and the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP). HSP is a rare presentation in ATP6-related disorders; mitochondrial ATP6-induced HSP has previously been published in only one family carrying a homoplasmic m.9176T > C [p.(Leu217Pro)] variant.ConclusionThis report highlights the role of MT-ATP6 pathogenic variants in complex and pure HSP and raises the relevance of genetic testing of MT-ATP6 in undiagnosed cases of sporadic or maternally inherited HSP.

Keywords:  gait ataxia; genome; heteroplasmy; maternal transmission; mitochondrial diseases; muscle spasticity; polyneuropathy

DOI:  https://doi.org/10.1177/22143602251391068
Stem Cell Reports. 2025 Nov 13. pii: S2213-6711(25)00315-7. [Epub ahead of print] 102711

Advances and challenges in modeling Charcot-Marie-Tooth type 2A using iPSC-derived models.

Mafalda Rizzuti, Elisa Pagliari, Martina D'Agostino, Linda Ottoboni, Valeria Parente, Giacomo Pietro Comi, Stefania Corti, Federica Rizzo, Elena Abati.

  Charcot-Marie-Tooth type 2A (CMT2A) is an inherited sensory-motor axonopathy caused by mutations in the Mitofusin2 (MFN2) gene, coding for MFN2 protein. No curative treatment has been developed to date. The advent of induced pluripotent stem cell (iPSC) has provided unprecedented opportunities to understand complex neurological disorders. In CMT2A research, patient-specific iPSCs can be differentiated in motor and sensory neurons, thereby establishing reliable in vitro disease models. Here, we review current available iPSC-based models of CMT2A, focusing on pathogenetic insights derived from these studies and discussing challenges and potential of iPSC-derived models in elucidating disease mechanisms, providing innovative platforms for testing, and developing novel effective therapeutic strategies.

Keywords:  CMT2A; MFN2; iPSCs; motor neurons; sensory neurons

DOI:  https://doi.org/10.1016/j.stemcr.2025.102711
Cells. 2025 Oct 29. pii: 1698. [Epub ahead of print]14(21):

Developmental Differences in Myocardial Mitochondrial Reticulum Networks in the Offspring Exposed to Diabetic Pregnancy.

Prathapan Ayyappan, Tyler C T Gandy, David Sturdevant, Tricia D Larsen, Pradeeksha Mukuntharaj, Andrew Paulson, Trace A Christensen, Jeffrey L Salisbury, Michelle L Baack.

  Diabetic pregnancy increases the offspring's risk of neonatal and adult cardiovascular disease (CVD). We previously used a rat model (Sprague-Dawley) to show that diabetic pregnancy impairs mitochondrial bioenergetics, dynamics, mitophagy, and quality control in the offspring's heart, and we hypothesized that mitochondrial dysfunction during early development influences the adult myocardium structure to confer cardiometabolic disease risk with aging. Here, we used 3D serial block face-scanning electron microscopy (SBF-SEM) to analyze perinuclear (PN) and intrafibrillar (IF) mitochondrial networks in the left ventricular sections from control and pregestational diabetes-exposed newborn (NB) rats that were three-week-old and four-month-old. Diabetes-exposed myocardium had 50% fewer PN and 20% fewer IF mitochondria at birth but counts increased more rapidly, resulting in no difference at three weeks and 35% more PN and 49% more IF mitochondria by four months. Despite rising counts, mitochondria volumes remained significantly lower at every developmental timepoint. This shows that diabetic pregnancy causes maldevelopment of the myocardial mitochondrial reticulum which likely contributes to adult CVD.

Keywords:  diabetic pregnancy; heart disease; mitochondrial dynamics; mitochondrial networks; myocardial development; myocardial reticulum

DOI:  https://doi.org/10.3390/cells14211698
J Physiol. 2025 Nov 10.

Developmental bioenergetics: a comparative perspective on mitochondrial efficiency in paediatric physiology.

Sébastien Ratel, Joffrey Bardin, Anthony J Blazevich.



Keywords:  efficiency; growth; metabolism; mitochondria; plasticity

DOI:  https://doi.org/10.1113/JP289900
J Extracell Vesicles. 2025 Nov;14(11): e70192

From Mitochondria to Immunity: The Emerging Roles of Mitochondria-Derived Vesicles and Small Extracellular Vesicles in Cellular Communication and Disease.

Rostyslav Horbay, Vasyl Syrvatka, Artem Bedzay, Mikaela van der Merwe, Dylan Burger, Shawn T Beug.

  According to the endosymbiotic theory of mitochondrial origin, an α-proteobacterium entered a prokaryotic cell and, through symbiosis, evolved into the mitochondria-the powerhouse of the cell. Like other bacteria, the α-proteobacteria generate their own extracellular vesicles (EVs), a trait that was passed onto the mitochondria, enabling them to generate mitochondria-derived vesicles (MDVs). MDVs, similar to small EVs (sEVs), are vesicles ranging from 30 to 200 nm in diameter and carry cargo for degradation by lysosomes and peroxisomes. MDVs share several features with sEVs, including targeted cargo degradation, biogenesis, packaging into multivesicular bodies, nucleic acid and protein transportation, induction of immune responses, and surface antigen presentation. MDVs may also be released from the cell in a manner similar to sEVs, potentially influencing intercellular communication and immune responses. Furthermore, the presence of MDVs presents opportunities for early disease detection, including neurodegenerative disorders and cancer. In this review, we explore the differences and similarities between MDVs and EVs, including their roles in immunity.

Keywords:  endosomal sorting complex required for transportation (ESCRT); endosome; lysosome; mitochondria‐derived vesicles (MDVs); mitophagy; multivesicular body (MVB); peroxisome; small extracellular vesicles (sEVs)

DOI:  https://doi.org/10.1002/jev2.70192
J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70113

STX4 Is Indispensable for Mitochondrial Homeostasis in Skeletal Muscle.

Joseph M Hoolachan, Rekha Balakrishnan, Erika M McCown, Karla E Merz, Chunxue Zhou, Elizabeth Bloom-Saldana, Patrick T Fueger, Angelica Hamilton, Tali Kiperman, Ke Ma, Eunjin Oh, Lei Jiang, Patrick Pirrotte, Orian Shirihai, Debbie C Thurmond.

   BACKGROUND: Mitochondrial homeostasis is vital for optimal skeletal muscle integrity. Mitochondrial quality control (MQC) mechanisms that are essential for maintaining proper functions of mitochondria include mitochondrial biogenesis, dynamics and mitophagy. Previously, Syntaxin 4 (STX4), traditionally considered a cell surface protein known for glucose uptake in skeletal muscle, was also identified at the outer mitochondrial membrane. STX4 enrichment was sufficient to reverse Type 2 diabetes-associated mitochondrial damage in skeletal muscle by inactivation of mitochondrial fission. However, whether STX4 could modulate skeletal muscle mitochondrial homeostasis through MQC mechanisms involving mitochondrial biogenesis or mitophagy remains to be determined.
METHODS: To determine the requirements of STX4 in mitochondrial structure, function and MQC processes of biogenesis and mitophagy, we implemented our in-house generated inducible skeletal muscle-specific STX4-knockout (skmSTX4-iKO) mice (Stx4fl/fl; Tg (HSA-rtTA/TRE-Cre)/B6) and STX4-depleted immortalized L6.GLUT4myc myotubes via siRNA knockdown (siSTX4).
RESULTS: We found that non-obese skmSTX4-iKO male mice (> 50% reduced STX4 abundance, soleus and gastrocnemius ***p < 0.001, tibialis anterior (TA) ****p < 0.0001) developed insulin resistance (**p < 0.01), together with reduced energy expenditure (AUC *p < 0.05), respiratory exchange ratio (AUC **p < 0.01) and grip strength (*p < 0.05). STX4 ablation in muscle also impaired mitochondrial oxygen consumption rate (****p < 0.0001). Mitochondrial morphological damage was heterogenous in STX4-depleted muscle, presenting with small fragmented mitochondria (****p < 0.0001) and decreased electron transport chain (ETC) abundance (CI ***p < 0.001, CII *p < 0.05, CIV **p < 0.01) in oxidative soleus muscle, whereas glycolytic-rich TA fibres displayed enlarged swollen mitochondria (****p < 0.0001) with no change in ETC abundance. Notably, > 60% reduction of STX4 in siSTX4 L6.GLUT4myc myotubes (****p < 0.0001) also decreased ETC abundance (CI **p < 0.01, CII ***p < 0.001, CIV **p < 0.01) without changes in mitochondrial glucose metabolism, as shown by [U-13C]glucose isotope tracing. For MQC, both skmSTX4-iKO male mice (*p < 0.05) and siSTX4 L6.GLUT4myc myotubes (*p < 0.05) showed decreased mitochondrial DNA levels alongside reduced mRNA expression of mitochondrial biogenesis genes Ppargc1a (PGC1-α, *p < 0.05) and Tfam (*p < 0.05) in skmSTX4-iKO soleus muscle and PGC1-α (mRNA **p < 0.01, protein *p < 0.05), NRF1 (mRNA **p < 0.01 and protein *p < 0.05) and Tfam (mRNA *p < 0.05) in siSTX4 L6.GLUT4myc myotubes. Furthermore, live cell imaging using the mt-Keima mitophagy biosensor in siSTX4 L6.GLUT4myc cells revealed significantly impaired mitochondrial turnover by mitophagy (*p < 0.05) and mitochondria-lysosome colocalization (*p < 0.05). STX4 depletion also reduced canonical mitophagy markers, PINK1 and PARKIN in both skmSTX4-iKO muscle (PARKIN *p < 0.05, PINK1 **p < 0.01) and siSTX4 L6.GLUT4myc myotubes (PARKIN **p < 0.01, PINK1 *p < 0.05).
CONCLUSIONS: Our study demonstrated STX4 as a key mitochondrial regulator required for mitochondrial homeostasis in skeletal muscle.

Keywords:  STX4; mitochondria; muscle; quality control

DOI:  https://doi.org/10.1002/jcsm.70113
Neurochem Res. 2025 Nov 10. 50(6): 354

Mitochondria-Mediated Mechanisms of Ferroptosis in Neurological Diseases.

Rujie Zhong, Hailin Yang, Xiaoyu Li, Feiyu Wang, Li Zhai, Jing Gao.

  Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, is increasingly recognized as a critical contributor to the pathogenesis of various neurological disorders. Mitochondria, the powerhouses of cells, play dual roles as both initiators and mediators of ferroptosis by integrating lipid peroxidation cascades, oxidative stress responses, and iron homeostasis dysregulation. This review first comprehensively explores the multifaceted mechanisms by which mitochondria mediate ferroptosis in neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Friedreich's ataxia (FRDA), amyotrophic lateral sclerosis (ALS), epilepsy, stroke, and brain injury, with a focus on mitochondrial lipid peroxidation and iron metabolism dysregulation. Building on these mechanistic insights, we further discuss emerging evidence suggesting that targeting mitochondrial pathways may represent a promising therapeutic strategy for mitigating ferroptosis-associated neuronal damage. By synthesizing these findings, our review establishes a conceptual foundation for developing innovative neuroprotective interventions through precise modulation of mitochondrial function within ferroptotic pathways.

Keywords:  Ferroptosis; Mitochondria; Neurological diseases; Reactive oxygen species

DOI:  https://doi.org/10.1007/s11064-025-04605-6
J Med Cases. 2025 Nov;16(11): 434-439

Perioperative Care of a Child With Combined Oxidative Phosphorylation Deficiency 6: Total Intravenous Anesthesia With Remimazolam.

Ifeoluwa C Olakunle, Joseph D Tobias.

  Combined oxidative phosphorylation deficiency 6 (COXPD6) is a severe mitochondrial encephalomyopathy resulting from a mutation in the X-linked apoptosis-inducing factor mitochondrion-associated 1 (AIFM1) gene. The AIFM1 gene located on chromosome Xq26.1, encodes apoptosis inducing factor (AIF), a flavin adenine dinucleotide (FAD)-dependent nicotinamide adenine dinucleotide (NADH) oxidoreductase, which is involved in the process of oxidative phosphorylation and mitochondrial-derived programmed cell death in the nucleus. COXPD6 patients have significant end-organ involvement of the central nervous, peripheral nervous, respiratory, and gastrointestinal systems, manifested by seizures, hypotonia, psychomotor delay, muscle weakness, and wasting. We present an 11-year-old child with AIFM1-related COXPD6 who underwent posterior spinal fusion for progressive neuromuscular kyphoscoliosis. We explore the genetic history of this mitochondrial disorder, review a detailed anesthetic approach to perioperative management including use of the novel benzodiazepine, remimazolam, and discuss anesthetic considerations in these patients.

Keywords:  AIFM1 gene; AIFM1-related combined oxidative phosphorylation deficiency 6; Mitochondrial disease; Pediatric anesthesiology

DOI:  https://doi.org/10.14740/jmc5179
Mitochondrion. 2025 Nov 11. pii: S1567-7249(25)00094-7. [Epub ahead of print]86 102097

Intravenous mitochondrial transplantation as an adjunctive therapy for dilated cardiomyopathy.

Tuğba Varlik, Didem Algan, Öner Sönmez, Keshav K Singh, Öner Ülger, Gökhan Burçin Kubat, Jørgen Koch, Zeki Yilmaz.

  Dilated cardiomyopathy (DCM) is one of the most prevalent myocardial disorders in various animals. The underlying causes of DCM are complex and often involve multiple contributing mechanisms. Mitochondrial dysfunction has been identified as a key factor in the progression of cardiomyocyte apoptosis. We investigated whether the transplantation of healthy mitochondria improves cardiac function by enhancing the contractile function of myocytes. A 6-year-old dog with cardiomyopathy received platelet-derived, viable mitochondria from a healthy donor as adjunctive therapy alongside standard medical management. Mitochondria were isolated from platelets and administered as a single intravenous bolus at a dose of 81,125 μg/mL. This procedure was carried out under continuous ECG and vital signs monitoring. Ventricular systolic function was assessed at multiple intervals using conventional echocardiography and two-dimensional speckle tracking imaging. Our study revealed notable improvement in systolic performance as early as two hours post-transplantation of mitochondria, with enhanced contractility sustained up to 24 h. These studies suggest mitochondrial transplantation may offer a promising intervention or adjunct to conventional treatments for cardiac dysfunction. This report presents the first documented case of intravenous mitochondrial transplantation in canine DCM.

Keywords:  Dilated cardiomyopathy; Mitochondrial transplantation; Speckle tracking echocardiography; Systolic myocardial dysfunction; Translational medicine

DOI:  https://doi.org/10.1016/j.mito.2025.102097
Mol Neurobiol. 2025 Nov 13. 63(1): 37

Development of Cellular Energy Metabolism During Differentiation of Human iPSCs into Cortical Neurons.

Šárka Danačíková, Petr Pecina, Alena Pecinová, Jan Svoboda, David Vondrášek, Davide Alessandro Basello, Tomáš Čajka, Daniel Hadraba, Tomáš Mráček, Vladimír Kořínek, Jakub Otáhal.

  Neuronal differentiation requires extensive metabolic remodeling to support increased energetic and biosynthetic demands. Here, we present an integrated multi-omics and functional characterization of metabolic transitions during early differentiation of human induced pluripotent stem cells (iPSCs) into excitatory cortical neurons using doxycycline-inducible overexpression of neurogenin-2 (NGN2). We analyzed parental iPSCs and induced neurons (iNs) at days 7 and 14 of differentiation, integrating gene expression profiling, label-free quantitative proteomics, high-resolution respirometry, fluorescence lifetime imaging microscopy (FLIM), and 13C₆-glucose metabolic flux analysis. Our data reveal progressive metabolic remodeling associated with neuronal maturation, including enhanced oxidative phosphorylation, increased mitochondrial content, and respiratory capacity. Proteomic analyses showed upregulation of mitochondrial and antioxidant pathways, while FLIM indicated a progressive increase in enzyme-bound NAD(P)H, consistent with a shift toward oxidative metabolism. Notably, 13C₆-glucose tracing revealed delayed labeling of the intracellular pool of fully labeled glucose and tricarboxylic acid cycle metabolites, together with enhanced labeling of pentose phosphate pathway intermediates and glutathione in iNs, indicating a shift toward biosynthetic and antioxidant glucose utilization during differentiation. Despite this enhancement in mitochondrial function, differentiated neurons maintained glycolytic activity, suggesting metabolic flexibility. Our results define the first week of differentiation as a critical window of metabolic specialization and establish NGN2-iPSC-derived cortical neurons as a versatile and well-characterized model system for investigating bioenergetic remodeling during early human neurodevelopment. It provides a robust foundation for mechanistic insights and high-throughput evaluation of metabolic pathways relevant to human disease.

Keywords:  Cellular bioenergetics; Human iPSCs; Metabolic flux analysis; Neuronal differentiation; Proteomics; Respirometry

DOI:  https://doi.org/10.1007/s12035-025-05284-8
Nat Commun. 2025 Nov 10. 16(1): 9875

Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition.

Ghayda M Mirzaa, Keqin Yan, Raissa Relator, Mathieu Levesque, Pranisha Jayasinghe, Sara Timpano, Binnaz Yalcin, Stephan Collins, Alban Ziegler, Emily Pao, Nora Oyama, Elise Brischoux-Boucher, Juliette Piard, Kristin G Monaghan, Maria J Guillen Sacoto, William B Dobyns, Kristen L Park, Daniel Martin Fernández-Mayoralas, Alberto Fernández-Jaén, Parul Jayakar, María Palomares-Bralo, Fernando Santos-Simarro, Alfredo Brusco, Vincenzo Antona, Elisa Giorgio, Malin Kvarnung, Bertrand Isidor, Solène Conrad, Benjamin Cogné, Wallid Deb, Kyra E Stuurman, Katalin Štěrbová, Noor Smal, Sarah Weckhuysen, Renske Oegema, A Micheil Innes, Daniel C Koboldt, Tawfeg Ben-Omran, Rebecca C Yeh, Michael C Kruer, Somayeh Bakhtiari, Antigone Papavasiliou, Sébastien Moutton, Sophie Nambot, Sirisak Chanprasert, Sarah A Paolucci, Kait Miller, Barbara Burton, Katherine Kim, Emily O'Heir, Zandre Bruwer, Kirsten A Donald, Tjitske Kleefstra, Amy Goldstein, Brad Angle, Kelly Bontempo, Peter Miny, Pascal Joset, Florence Demurger, Emma Hobson, Lewis Pang, Lori Carpenter, Dong Li, Dominique Bonneau, Bekim Sadikovic, David J Picketts.

Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SMARCA5 or SMARCA1 ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 have been previously implicated in NDDs. Here, we describe 35 individuals from 26 families with de novo or maternally inherited variants in the X-linked SMARCA1 gene. This SMARCA1-related NDD is associated with a spectrum of involvement, including mild to severe ID/DD, delayed or regressive speech development, ASD features, facial dysmorphisms, and other variable features. Individuals carrying SMARCA1 truncating variants exhibit a mildly unique genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptf single and double mouse knockouts reveals the importance of NURF composition and dosage for proper forebrain development. We propose that genetic alterations affecting different NURF components, including SMARCA1, result in a NDD with a broad clinical spectrum.

DOI: https://doi.org/10.1038/s41467-025-64838-5
Nat Commun. 2025 Nov 14. 16(1): 10031

Intrinsic dysfunction in muscle stem cells lacking dystrophin begins during secondary myogenesis.

Marie E Esper, Alexander Y T Lin, Dallas Bennett, Michael A Rudnicki.

Loss of dystrophin causes Duchenne Muscular Dystrophy (DMD), a neuromuscular disease characterized by muscle fragility and muscle stem cell (MuSC) impairment. Conventional understanding is that DMD manifests after birth from cumulative muscle damage. Here, examination of mdx mouse embryos lacking dystrophin reveals no impairment of the primary myogenic program. By contrast, histological and single cell RNA-sequencing analysis during secondary myogenesis uncovers an increase in the proportion of fetal (f) MuSCs and a marked reduction in myogenic progenitors and myocytes, leading to fewer smaller-caliber myofibers. Wild type fMuSCs express full-length dystrophin that interacts with MARK2, whereas mdx fMuSCs downregulate MARK2 and NUMB, exhibiting reduced PARD3 polarization. Strikingly, deletion of the Numb Associated Kinase, AAK1, rescues polarization of NUMB and myogenic progenitor generation in mdx fetal muscle. Together, our results elucidate an acute disease pathology during DMD fetal development and the potential for therapeutic intervention by targeting AAK1.

DOI: https://doi.org/10.1038/s41467-025-64999-3
Sci Adv. 2025 Nov 14. 11(46): eadu0726

CHCHD2 mutant mice link mitochondrial deficits to PD pathophysiology.

Szu-Chi Liao, Kohei Kano, Sadhna Phanse, Mai Nguyen, Elyssa Margolis, YuHong Fu, Jonathan X Meng, Mohamed Taha Moutaoufik, Zac Chatterton, Tatiana Saccon, Kirsten Broderick, Hiroyuki Aoki, Jeffrey Simms, Felicia Xaveria Suteja, Yoshitaka Sei, Eric J Huang, Kevin McAvoy, Giovanni Manfredi, Glenda Halliday, Mohan Babu, Ken Nakamura.

Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2 (coiled-coil-helix-coiled-coil-helix domain-containing 2), which causes late-onset symptoms indistinguishable from idiopathic PD. We observed pronounced mitochondrial disruption in substantia nigra dopaminergic neurons, including distorted ultrastructure and CHCHD2 aggregation, as well as disrupted mitochondrial protein-protein interactions in brain lysates. These abnormalities were associated with a whole-body metabolic shift toward glycolysis, elevated mitochondrial reactive oxygen species (ROS), and progressive accumulation of aggregated α-synuclein. In idiopathic PD, CHCHD2 gene expression also correlated with α-synuclein levels in vulnerable dopaminergic neurons, and CHCHD2 protein accumulated in early Lewy aggregates. These findings delineate a pathogenic cascade in which CHCHD2 accumulation impairs mitochondrial respiration and increases ROS production, driving α-synuclein aggregation and neurodegeneration.

DOI: https://doi.org/10.1126/sciadv.adu0726
Ultrasound Med Biol. 2025 Nov 12. pii: S0301-5629(25)00392-8. [Epub ahead of print]

Longitudinal Ultrasound Imaging of an Individual Fetus In Utero Using an Echogenic Marker.

Ruiyan Tan, Sarah K Debebe, Owen Botelho, Cameron Goddard, Brian J Nieman, John G Sled.

   OBJECTIVE: High frequency ultrasound imaging has become an important tool for the study of pregnancy disorders in mouse models as it enables detailed, noninvasive characterization of in utero development. However, the need to reliably identify individual fetuses over time presents a challenge when using this approach for longitudinal assessments. Large litter sizes and frequently changing fetal positions within the abdomen across gestation have the potential to confound such measurements.
METHOD: The current study presents a minimally invasive method to longitudinally track a specific mouse fetus through late gestation using ultrasound-guided intra-amniotic injections of an echogenic marker comprised of glass microspheres and shear thinning biomaterial, on embryonic day (E)14.5. Longitudinal measurements of the umbilical artery blood flow were gathered to assess feasibility of a plausible experiment in fetal research. Fetal lung volumes were collected to assess safety of the intra-amniotic sac injection and procedure as amniotic fluid loss during injection risks underdeveloped lungs.
RESULTS: Using CD-1 strain mice, we show that key diagnostic parameters such as umbilical artery velocity and vessel diameter, can be repeatedly measured in the tracked fetus from E14.5 through to term (E18.5). The method is safe for the fetus and pregnant dam with no increased mortality.
CONCLUSION: Combining this method of mouse fetal tracking with established mouse models of pregnancy-related and gestational conditions proves to be a reliable method for longitudinal data collection in mouse fetuses.

Keywords:  Embryo imaging; High frequency ultrasound; Longitudinal imaging; Mouse model

DOI:  https://doi.org/10.1016/j.ultrasmedbio.2025.10.003