bims-mitmed 2025-11-30 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–11–30
twenty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

In vivo mitochondrial base editing restores genotype and visual function in a mouse model of LHON.
Canonical and non-canonical functions of proteins regulating mitochondrial dynamics in mammalian physiology.
Mitochondrial Base Editing of the m.8993T>G Mutation Restores Bioenergetics and Neural Differentiation in Patient iPSCs.
MICU2 controls mitochondrial calcium signaling and migration in neurons during development.
Kidney transplantation in mitochondrial diseases: a systematic review.
Drug repurposing screen identifies an HRI activating compound that promotes adaptive mitochondrial remodeling in MFN2-deficient cells.
APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling.
From Congenital Torticollis to Leigh Syndrome: A Case Report of Diagnostic Evolution in an Infant.
A metabolic atlas of mouse aging.
Metformin promotes mitochondrial integrity through AMPK-signaling in Leber's hereditary optic neuropathy.
NAD+ restores proteostasis through splicing-dependent autophagy.
Localized Wnt-signaling promotes asymmetric NuMA-dependent oriented divisions and unequal apportioning of mitochondria.
Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
Mitochondrial Quality Control and Cell Death.
Dysregulated Fatty Acid Metabolism in Preeclampsia Among Highland Andeans: Insights Into Adaptive and Maladaptive Placental Metabolic Phenotypes.
Mitochondria-Enriched Extracellular Vesicles (EVs) for Cardiac Bioenergetics Restoration: A Scoping Review of Preclinical Mechanisms and Source-Specific Strategies.
Distinct Neurodegenerative Pathways in Two NBIA Subtypes: Inflammatory Activation in C19orf12 but Not in PANK2 Mutation Carriers.
Mitochondrial DNA Deletions and Plasma GDF-15 Protein Levels Are Linked to Hormonal Dysregulation and Multi-Organ Involvement in Female Reproductive Endocrine Disorders.
Metabolic reprogramming and altered ATP content impair neuroprotective functions of microglia in β-glucocerebrosidase deficiency models.
Prenatal Diagnosis of COQ2 Variants in Suspected Coenzyme Q10 Deficiency.

Nat Commun. 2025 Nov 23.

In vivo mitochondrial base editing restores genotype and visual function in a mouse model of LHON.

Sanghun Kim, Jieun Kim, Seongkwang Cha, Sungjin Ju, Chae Jin Lim, Seongho Hong, Jiyoung Bae, Yeji Oh, Sungmo Jung, Sol Pin Kim, Hae-Sol Shin, Jae Hee Yoon, Jeeyoon Park, Seungmin Ryou, Soo-Yeon Lim, Su Bin Lee, Seung Hee Choi, Soo-Ji Park, Chang Geun Choi, Mihyun Choi, Lark Kyun Kim, Jiyoon Park, Seonghyun Lee, Kyoung Yul Seo, Je Kyung Seong, Kyoungmi Kim, Jin-Soo Kim, Hyunji Lee.

Leber hereditary optic neuropathy (LHON), a maternally inherited mitochondrial disorder, results from point mutations in mitochondrial DNA (mtDNA), primarily affecting the MT-ND4 gene. To date, no animal model harboring authentic LHON mutations has been available, limiting therapeutic development. However, when we attempted to generate such models using mitochondrial base editors, we found that activity-enhanced DddA11-based cytosine base editors (DdCBEs) induce off-target mtDNA mutations and developmental arrest in embryos. Using a high-fidelity DdCBE (Hifi-DdCBE), we successfully generate mice carrying the pathogenic MT-ND4 G11778A mutation, the most common LHON variant. These mice exhibit hallmark phenotypes, including retinal ganglion cell loss and impaired visual function. Intravitreal delivery of adeno-associated virus encoding TALE-linked deaminases (TALEDs) restores both phenotype and genotype in these mice. Furthermore, optimized TALEDs corrects the ND4 mutation with minimal off-target effects in LHON patient-derived cells, highlighting the potential of mitochondrial base editing as a therapeutic strategy for mtDNA-associated diseases.

DOI: https://doi.org/10.1038/s41467-025-66600-3
J Physiol. 2025 Nov 22.

Canonical and non-canonical functions of proteins regulating mitochondrial dynamics in mammalian physiology.

Rémi Chaney, Vincent Marcangeli, Krystel Desjardins, Shima Taherkhani, Gilles Gouspillou.

  Mitochondria are dynamic and multifunctional organelles central to cellular bioenergetics and metabolism and acting as vital signalling hubs. Their morphology is finely regulated by the opposing processes of fusion and fission, predominantly controlled by four key GTPases: mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (DRP1). In humans, mutations in their genes are linked to a broad range of pathological disorders. In animal models, both loss- and gain-of-function manipulations of these proteins lead to diverse physiological outcomes. Recent research has uncovered that, beyond their canonical roles in shaping mitochondrial morphology, these GTPases also participate in a variety of non-canonical cellular functions, impacting broader aspects of cell physiology. In this review, we examine the established functions of these GTPases in mitochondrial dynamics alongside their emerging roles beyond shaping mitochondrial morphology. We also provide an in-depth overview of how alterations in their expression or activity influence mammalian health and physiology. By highlighting the multifaceted roles and broad physiological impact of mitochondrial fusion and fission proteins, we aim to underscore their complex biology and promote further investigation into their broader physiological significance.

Keywords:  GTPases; Mitofusins; dynamin‐related protein 1; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitochondrial quality control; optic atrophy 1

DOI:  https://doi.org/10.1113/JP287149
Genes (Basel). 2025 Nov 01. pii: 1298. [Epub ahead of print]16(11):

Mitochondrial Base Editing of the m.8993T>G Mutation Restores Bioenergetics and Neural Differentiation in Patient iPSCs.

Luke Yin, Angel Yin, Marjorie Jones.

   BACKGROUND: Point mutations in mitochondrial DNA (mtDNA) cause a range of neurometabolic disorders that currently have no curative treatments. The m.8993T>G mutation in the Homo sapiens MT-ATP6 gene leads to neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) when heteroplasmy exceeds approximately 70%.
METHODS: We engineered a split DddA-derived cytosine base editor (DdCBE), each half fused to programmable TALE DNA-binding domains and a mitochondrial targeting sequence, to correct the m.8993T>G mutation in patient-derived induced pluripotent stem cells (iPSCs). Seven days after plasmid delivery, deep amplicon sequencing showed 35 ± 3% on-target C•G→T•A conversion at position 8993, reducing mutant heteroplasmy from 80 ± 2% to 45 ± 3% with less than 0.5% editing at ten predicted off-target loci.
RESULTS: Edited cells exhibited a 25% increase in basal oxygen consumption rate, a 50% improvement in ATP-linked respiration, and a 2.3-fold restoration of ATP synthase activity. Directed neural differentiation yielded 85 ± 2% Nestin-positive progenitors compared to 60 ± 2% in unedited controls.
CONCLUSIONS: Edits remained stable over 30 days in culture. These results establish mitochondrial base editing as a precise and durable strategy to ameliorate biochemical and cellular defects in NARP patient cells.

Keywords:  DdCBE; MT-ATP6; NARP; base editing; heteroplasmy; iPSCs; m.8993T>G; mitochondrial DNA

DOI:  https://doi.org/10.3390/genes16111298
Cell Rep. 2025 Nov 20. pii: S2211-1247(25)01355-5. [Epub ahead of print]44(12): 116583

MICU2 controls mitochondrial calcium signaling and migration in neurons during development.

Elena Berezhnaya, Benjamín Cartes-Saavedra, Raghavendra Singh, Macarena Rodríguez-Prados, Orly Reiner, Fowzan S Alkuraya, György Hajnóczky.

  Neurological disorders are linked to mitochondrial dysfunction and calcium overload. Mitochondrial calcium uptake is mediated by the mitochondrial calcium uniporter (mtCU), regulated by MICU1, which can be either homodimerized or heterodimerized with MICU2 or MICU3. Though MICU2 is scarce in the adult brain, MICU2 loss in patients leads to a neurodevelopmental disorder. We hypothesized that MICU2 is required for developmental calcium signaling and neuronal migration. MICU2 is present in the developing mouse brain but disappears by maturation, contrasting with other mtCU subunits that increase. MICU2 loss in mice does not affect cytoplasmic calcium but augments the mitochondrial matrix calcium rise in primary cortical neurons, leading to neuronal overmigration in the cortex and behavioral changes at 2 but not 12 months. Consistently, mitochondrial calcium uptake is not significantly affected in the adult animal cortex. MICU2-deficient patient fibroblasts copy the mitochondria-confined calcium alteration in developing neurons. Thus, MICU2 is important during neurodevelopment, likely by regulating the mtCU, and is eliminated by brain maturation.

Keywords:  CP: cell biology; CP: neuroscience; MCU; MICU2; MICU3; anxiety; brain development; calcium signaling; mitochondria; neurodevelopmental disorders; neurons; radial migration

DOI:  https://doi.org/10.1016/j.celrep.2025.116583
Pediatr Nephrol. 2025 Nov 27.

Kidney transplantation in mitochondrial diseases: a systematic review.

Sze Wa Wong, Cheuk Wing Fung, Fred Tomlin, Jelena Stojanovic.

   BACKGROUND: Primary mitochondrial diseases are a group of rare, heterogeneous, multisystem disorders. While renal involvement is increasingly recognised, especially in paediatric patients, data on kidney transplantation outcomes in this population remain limited.
OBJECTIVES: To evaluate kidney transplantation outcomes in genetically confirmed primary mitochondrial diseases with multi-organ involvement and provide clinical insights from systematic literature review.
DATA SOURCES: We systematically searched PubMed, MEDLINE, EMBASE and Google Scholar from inception to 10 June 2025 using keywords and MeSH terms related to "mitochondrial disease", "transplantation" and "outcome".
STUDY ELIGIBILITY CRITERIA: We included studies that reported post-transplant clinical outcomes in patients with genetically confirmed primary mitochondrial diseases. Studies without genetic confirmation or transplant follow-up were excluded. Patients with Co-enzyme Q 10 deficiency were excluded as they mainly manifest as isolated steroid resistant nephrotic syndrome with subtypes that respond well to co-enzyme replacement.
PARTICIPANTS AND INTERVENTIONS: Participants included paediatric or adult patients diagnosed with genetically confirmed primary mitochondrial diseases who received isolated kidney transplant from living or deceased donor.
STUDY APPRAISAL AND SYNTHESIS METHODS: Data were extracted on demographics, genotypes, renal and extra-renal features, transplant characteristics, complications and outcomes. Risk of bias was assessed qualitatively by two independent reviewers. Discrepancies were resolved through consensus or discussion with third reviewer. Due to clinical and methodological heterogeneity, a narrative synthesis was performed.
RESULTS: Forty-six patients (15 paediatric, 31 adult) were included from 18 eligible studies. Ten patients had RMND1-related disease. All harboured either homozygous or compound heterozygous c.713A > G variants in RMND1. Thirty patients carried the m.3243A > G mtDNA point mutation variant in MT-TL1. The remaining six patients harboured an m.3271 T > C variant in MT-TL1, single mtDNA deletions, m.8618dup in MT-ATP6, m.12418delA in MT-ATP6 and m.13513G > A in MT-ND5 respectively. At nephrology referral, chronic kidney disease and kidney failure each was present in 26.1% of patients. Median time from renal presentation to kidney failure was 6 years. Graft and patient survival exceeded 90% across different genetic mutations and age groups. Post-transplant deterioration of neurological or metabolic features was reported predominantly in patients with an m.3243A > G variant.
LIMITATIONS: The review is limited by small sample size, selection and reporting bias, heterogeneous follow-up durations and outcome measures. Data were derived mainly from case reports and small case series.
CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Kidney transplantation is a viable option of kidney replacement therapy for patients with mitochondrial diseases. Patients with primary mitochondrial diseases should be considered for kidney transplantation. Further prospective studies are needed to define optimal transplant timing, immunosuppression strategies and long-term systemic outcomes.
SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD420251086889.

Keywords:  Kidney failure kidney transplantation; Patient survival; Primary mitochondrial diseases

DOI:  https://doi.org/10.1007/s00467-025-07034-3
Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2517552122

Drug repurposing screen identifies an HRI activating compound that promotes adaptive mitochondrial remodeling in MFN2-deficient cells.

Prerona Bora, Mashiat Zaman, Samantha Oviedo, Sergei Kutseikin, Nicole Madrazo, Prakhyat Mathur, Meera Pannikkat, Sophia Krasny, Rama Aldakhlallah, Alan Chu, Kristen A Johnson, Danielle A Grotjahn, Timothy E Shutt, R Luke Wiseman.

  Pathogenic variants in the mitochondrial outer membrane GTPase MFN2 cause the peripheral neuropathy Charcot-Marie-Tooth type 2A (CMT2A). These mutations can disrupt MFN2-dependent regulation of diverse aspects of mitochondrial biology including organelle morphology, motility, mitochondrial-endoplasmic reticulum (ER) contacts (MERCs), and respiratory chain activity. However, no therapies currently exist to mitigate the mitochondrial dysfunction linked to genetic deficiencies in MFN2. Herein, we performed a drug repurposing screen to identify compounds that selectively activate the integrated stress response (ISR)-the predominant stress-responsive signaling pathway responsible for regulating mitochondrial morphology and function. This screen identified the compounds parogrelil and MBX-2982 as potent and selective activators of the ISR through the OMA1-DELE1-HRI signaling axis. We show that treatment with these compounds promotes adaptive, ISR-dependent remodeling of mitochondrial morphology and protects mitochondria against genetic and chemical insults. Moreover, we show that pharmacologic ISR activation afforded by parogrelil restores mitochondrial tubular morphology, promotes mitochondrial motility, rescues MERCs, and enhances mitochondrial respiration in MFN2-deficient cells. These results demonstrate the potential for pharmacologic ISR activation through the OMA1-DELE1-HRI signaling pathway as a potential strategy to mitigate mitochondrial dysfunction in CMT2A and other pathologies associated with MFN2 deficiency.

Keywords:  drug repurposing; integrated stress response; mitochondrial dysfunction

DOI:  https://doi.org/10.1073/pnas.2517552122
Free Radic Biol Med. 2025 Nov 21. pii: S0891-5849(25)01385-1. [Epub ahead of print]243 245-259

APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling.

Firoz Akhter, Asma Akhter, Donghui Zhu.

  APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease (AD), is closely associated with mitochondrial dysfunction, yet the mechanisms remain poorly defined. We identify a previously unrecognized failure of the Nrf2-PINK1/Parkin axis in APOE4 neurons that compromises mitochondrial quality control. Unlike APOE3, APOE4 neurons fail to activate PINK1/Parkin-dependent mitophagy under stress, a defect compounded by impaired Nrf2 signaling and weakened antioxidant defenses. In vivo, APOE4 mice show age-dependent collapse of this pathway, correlating with progressive mitochondrial dysfunction and disrupted mito-nuclear communication. Pharmacological activation of Nrf2 or PINK1 restores mitochondrial clearance, highlighting the axis as a druggable node. These findings provide a mechanistic link between APOE4 and mitochondrial failure, establishing the Nrf2-PINK1/Parkin pathway as a critical driver of neurodegeneration and a promising target for therapeutic intervention in AD.

Keywords:  APOE4; Alzheimer's disease (AD); Mito-nuclear communication; Mitochondrial stress; Mitophagy; Nrf2-PINK/Parkin

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.040
Children (Basel). 2025 Nov 10. pii: 1522. [Epub ahead of print]12(11):

From Congenital Torticollis to Leigh Syndrome: A Case Report of Diagnostic Evolution in an Infant.

Minsoo Jeon, Shin-Seung Yang, Sera Lee, Ja Young Choi.

  Leigh syndrome is a rare, progressive mitochondrial disorder of childhood. Early diagnosis is often challenging due to nonspecific clinical manifestations. We report a 1-month-old male infant initially referred for suspected congenital muscular torticollis who ultimately received a diagnosis of Leigh syndrome. Despite unremarkable perinatal history, he subsequently developed persistent feeding difficulties, recurrent vomiting, failure to thrive, and global developmental delay. Early neurological assessment revealed poor repertoire patterns on General Movement Assessment. The Neonatal Oral-Motor Assessment Scale (NOMAS) demonstrated dysfunctional oral-motor control, whereas the video fluoroscopic swallowing study (VFSS) revealed aspiration during swallowing. Brain MRI revealed symmetric basal ganglia lesions. Expanded whole-exome sequencing identified a pathogenic MT-ATP6 m.8993T>G variant with high heteroplasmy level (>90% in blood), confirming the diagnosis of Leigh syndrome. The variant was maternally inherited, although neither the mother nor the older sibling exhibited clinical features of mitochondrial disease. Leigh syndrome can initially manifest with subtle systemic features rather than overt neurological features. Persistent feeding difficulties and growth delay in infancy warrant thorough evaluation, including neuroimaging and comprehensive genomic testing, to enable timely diagnosis and optimize clinical management.

Keywords:  Leigh syndrome; MT-ATP6; feeding difficulties; global developmental delay; mitochondria; torticollis

DOI:  https://doi.org/10.3390/children12111522
Cell Metab. 2025 Nov 25. pii: S1550-4131(25)00476-0. [Epub ahead of print]

A metabolic atlas of mouse aging.

Steven E Pilley, Dominik Awad, Djakim Latumalea, Connie New, Edgar Esparza, Shuo Wang, Xuanyi Shi, Li Zhang, Maximilian Unfried, Jasinda H Lee, Ernst Schmid, Ipsita Mohanty, Jenna L E Blum, Shivaanishaa Raventhiran, Esther Wong, Preeti R Iyengar, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Peter Sajjakulnukit, Damien Sutton, Harrison K A Wong, Yaqi Gao, George Wang, Aeowynn J Coakley, Gilberto Garcia, Ryo Higuchi-Sanabria, Anja Karlstaedt, Timothy L Frankel, Marina Pasca di Magliano, Whitaker Cohn, Sophia Liu, Bingfei Yu, Pieter C Dorrestein, Ernest Fraenkel, Shawn M Davidson, William B Tu, Brian K Kennedy, Costas A Lyssiotis, Peter J Mullen.

  Humans are living longer and experiencing more age-related diseases, many of which involve metabolic dysregulation, but how metabolism changes in multiple organs during aging is not known. Answering this could reveal new mechanisms of aging and therapeutics. Here, we profile metabolic changes in 12 organs in male and female mice at 5 different ages. We also develop organ-specific metabolic aging clocks that identify metabolic drivers of aging, including alpha-ketoglutarate, previously shown to extend lifespan in mice. We also use the clocks to uncover that carglumic acid is a potential driver of aging and show that it is synthesized by human cells. Finally, we validate that hydroxyproline decreases with age in the human pancreas, emphasizing that our approach reveals insights across species. This study reveals fundamental insights into the aging process and identifies new therapeutic targets to maintain organ health.

Keywords:  LC-MS/MS; MALDI-MSI; aging; aging clocks; healthspan; human tissue; hydroxyproline; metabolism; scRNA-seq; sex

DOI:  https://doi.org/10.1016/j.cmet.2025.10.016
FEBS Open Bio. 2025 Nov 23.

Metformin promotes mitochondrial integrity through AMPK-signaling in Leber's hereditary optic neuropathy.

Chatnapa Panusatid, Rapasviranda Soiyangsuk, Maneeluck Tanadjindarat, Chayanon Peerapittayamongkol.

  Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder caused by mitochondrial DNA mutations in complex I of the respiratory chain, leading to impaired ATP production, mitochondrial fragmentation, and oxidative stress that contribute to vision loss. This study investigated the potential repurposing of metformin, a widely used antidiabetic drug, in fibroblasts from LHON patients carrying the m.11778G>A mutation. Fibroblasts from LHON patients and healthy individuals were treated with metformin, and mitochondrial function was assessed using high-content imaging, biochemical assays, immunoblotting, immunofluorescence, and Seahorse analysis. Metformin reduced mitochondrial fragmentation, increased network length, stabilized mitochondrial membrane potential, enhanced ATP production, and lowered ROS accumulation under oxidative stress. Metformin significantly increased mitophagy and autophagic flux, as shown by LC3B puncta quantification with and without chloroquine, and activated AMPK signaling through increased AMPKα1/2 phosphorylation and AMPKβ1 Ser182 phosphorylation. In addition, metformin promoted PGC-1α nuclear translocation, indicating stimulation of mitochondrial biogenesis, while maintaining mtDNA copy number and supporting oxidative phosphorylation. These findings suggest that metformin, at clinically relevant concentrations, enhances mitochondrial health and function in LHON fibroblasts, supporting its potential as an affordable and safe therapeutic option to mitigate vision loss in LHON.

Keywords:  AMPK activation; Leber's hereditary optic neuropathy; Metformin; Mitochondrial dynamics; Mitophagy; Primary fibroblasts

DOI:  https://doi.org/10.1002/2211-5463.70165
Autophagy. 2025 Nov 28.

NAD+ restores proteostasis through splicing-dependent autophagy.

Ruixue Ai, Evandro F Fang.

  Autophagy preserves neuronal integrity by clearing damaged proteins and organelles, but its efficiency declines with aging and neurodegeneration. Depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) is a hallmark of this decline, yet how metabolic restoration enhances autophagic control has remained obscure. Meanwhile, alternative RNA splicing errors accumulate in aging brains, compromising proteostasis. Here, we identify a metabolic - transcriptional mechanism linking NAD+ metabolism to autophagic proteostasis through the NAD+ -EVA1C axis. Cross-species analyses in C. elegans, mice, and human samples reveal that NAD+ supplementation corrects hundreds of age- or Alzheimer-associated splicing errors, notably restoring balanced expression of EVA1C isoforms. Loss of EVA1C impairs the memory and proteostatic benefits of NAD+, underscoring its essential role in neuronal resilience. Mechanistically, NAD+ rebalances EVA1C isoforms that interact with chaperones BAG1 and HSPA/HSP70, reinforcing their network to facilitate chaperone-assisted selective autophagy and proteasomal degradation of misfolded proteins such as MAPT/tau. Thus, NAD+ restoration coordinates RNA splicing fidelity with downstream proteostatic systems, establishing a metabolic - transcriptional checkpoint for neuronal quality control. This finding expands the paradigm of autophagy regulation, positioning metabolic splice-switching as a crucial mechanism to maintain proteostasis and suggesting new strategies to combat aging-related neurodegenerative diseases.

Keywords:  Aging; NAD+ precursors; alzheimer disease; machine learning; rna splicing; tauopathy

DOI:  https://doi.org/10.1080/15548627.2025.2596679
Nat Commun. 2025 Nov 27. 16(1): 10690

Localized Wnt-signaling promotes asymmetric NuMA-dependent oriented divisions and unequal apportioning of mitochondria.

Susanna Eli, Greta Rauso, Paola Ghezzi, James L A Szczerkowski, Michela Bruzzi, Francesca Rizzelli, Fabiola Iommazzo, Alessia Loffreda, Francesco Castagna, Federico Donà, Chiara Gaddoni, Ambra Dondi, Mattia Marenda, Simona Rodighiero, Pierre Tournier, Zeno Lavagnino, Dario Parazzoli, Nils C Gauthier, Simone Tamburri, Diego Pasini, Shukry James Habib, Marina Mapelli.

In multicellular organisms, the execution of developmental and homeostatic programs often relies on asymmetric cell divisions. These divisions require the alignment of the mitotic spindle axis to cortical polarity cues, and the unequal partitioning of cellular components between progeny cells. Asymmetric divisions are orchestrated by signals from the niche frequently presented in a directional manner, such as Wnt signals. Here we employ bioengineered Wnt-niches to demonstrate that in metaphase NuMA/dynein microtubule motors form a complex with activated LRP6 and β-catenin at the cortical sites of Wnt activation to orient cell division perpendicularly. We show that engagement of LRP6 co-receptors by Wnt ligands locally stabilizes actomyosin contractility through the accumulation of myosin1C. Additionally, we describe a proteomic-based approach to identify mitotic protein complexes enriched at the Wnt-contact site, revealing that mitochondria polarize toward localized Wnt3a sources and are asymmetrically apportioned to the Wnt-proximal daughter cell during Wnt-mediated asymmetric cell division of embryonic stem cells. Mechanistically, we show that CENP-F is required for mitochondria polarization towards localized sites of Wnt3a activation, and that deletion of the Wnt-co-receptor LRP6 impairs the asymmetric apportioning of mitochondria. Our findings enhance the understanding of mitotic Wnt-signaling and elucidate fundamental principles underlying Wnt-dependent mitochondrial polarization.

DOI: https://doi.org/10.1038/s41467-025-65775-z
Nat Commun. 2025 Nov 28. 16(1): 10761

Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.

Candice Kutchukian, Maria Casas, Rose E Dixon, Eamonn J Dickson.

Lysosomes are essential organelles that regulate cellular homeostasis through complex membrane interactions. Phosphoinositide lipids play critical roles in orchestrating these functions by recruiting specific proteins to organelle membranes. The PIKfyve/Fig4/Vac14 complex regulates PI(3,5)P₂ metabolism, and intriguingly, while loss-of-function mutations cause neurodegeneration, acute PIKfyve inhibition shows therapeutic potential in neurodegenerative disorders. We demonstrate that PIKfyve/Fig4/Vac14 dysfunction triggers a compensatory response where reduced mTORC1 activity leads to ULK1-dependent trafficking of ATG9A and PI4KIIα from the TGN to lysosomes. This increases lysosomal PI(4)P, facilitating cholesterol and phosphatidylserine transport at ER-lysosome contacts to promote membrane repair. Concurrently, elevated lysosomal PI(4)P recruits ORP1L to ER-lysosome-mitochondria three-way contacts, enabling PI(4)P transfer to mitochondria that drives ULK1-dependent fragmentation and increased respiration. These findings reveal a role for PIKfyve/Fig4/Vac14 in coordinating lysosomal repair and mitochondrial homeostasis, offering insights into cellular stress responses.

DOI: https://doi.org/10.1038/s41467-025-65798-6
Int J Mol Sci. 2025 Nov 16. pii: 11084. [Epub ahead of print]26(22):

Mitochondrial Quality Control and Cell Death.

Zurui Zhang, Mengyuan Zhang, Hongchi Jin, Shuang Lv, Yilei Li, Yanru Li.

  Mitochondrial quality control includes mitochondrial biogenesis, fusion, fission (to maintain mitochondrial function), and mitochondrial autophagy (for removing damaged mitochondria). This is a highly delicate and complex process involving many molecules. Mitochondrial quality control is crucial for maintaining mitochondrial homeostasis and function, preserving energy supply, eliminating damaged mitochondria to prevent cytotoxicity, promoting mitochondrial regeneration and repair, protecting cells from oxidative stress and senescence, and facilitating cellular communication and material exchange. In this review, we introduce the structure and function of mitochondria, the mechanisms of quality control, and the relationship between mitochondrial quality control and cellular processes such as pyroptosis, apoptosis, and ferroptosis. We also summarize the proteins, enzymes, and their molecular mechanisms involved in these processes and propose a "spatiotemporal-threshold" model for the mitochondrial quality control-cell death axis.

Keywords:  apoptosis; ferroptosis; mitochondrial autophagy; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitochondrial quality control; pyroptosis

DOI:  https://doi.org/10.3390/ijms262211084
FASEB J. 2025 Nov 30. 39(22): e71254

Dysregulated Fatty Acid Metabolism in Preeclampsia Among Highland Andeans: Insights Into Adaptive and Maladaptive Placental Metabolic Phenotypes.

Katie A O'Brien, Lilian Toledo-Jaldin, Wanjun Gu, Julie A Houck, Litzi Lazo-Vega, Valquiria Miranda-Garrido, Hong W Yung, Hussna Yasini, Lorna G Moore, Julie A Reisz, Tatum S Simonson, Jonathan Shortt, Margaret Stalker, Angelo D'Alessandro, Colleen G Julian.

  High-altitude pregnancy presents the complex physiological challenge of fulfilling maternal, placental, and fetal metabolic demands under chronic ambient hypoxia. Highland Andeans exhibit signs of adaptation to high-altitude hypoxia, showing relative protection against altitude-associated fetal growth restriction (FGR) and the positive selection of metabolic genes linked to placental mitochondrial capacity. Not all infants are protected, with both FGR and preeclampsia occurring among highland-resident Andeans. In Andeans, placental metabolic dysfunction is evident. By integrating metabolomic studies of maternal-placental-fetal triads with adaptive genetic signals in the fetal genome, we sought to identify adaptive and maladaptive placental metabolic phenotypes in highland Andeans (La Paz, Bolivia; 3850 m), including normotensive and preeclamptic pregnancies. Widespread differences in metabolite abundance were evident between normotensive and preeclamptic pregnancy across maternal, placental, and fetal compartments. Preeclampsia was characterized by a pronounced accumulation of fatty acid derivatives, specifically medium and long-chain acylcarnitines; these were also associated with low birth weight. Genotype-phenotype association analyses revealed novel links between putatively adaptive fetal haplotypes and placental metabolite abundance. Carriers of specific adaptive fetal haplotypes comprising genes linked to lipid metabolism had a greater abundance of placental short-chain acetyl-carnitine alongside decreased levels of linolenic acid (CPT2/LRP8), lower levels of the medium-chain octanoylcarnitine (EXOC4), and greater abundance of free carnitine (LIPG). Collectively, our study reveals a distinct metabolic phenotype in Andean preeclampsia characterized by incomplete fatty acid oxidation and highlights novel links between putatively adaptive fetal haplotypes and healthy placental metabolic phenotypes.

Keywords:  adaptation; hypertensive disorders of pregnancy; hypoxia; metabolome

DOI:  https://doi.org/10.1096/fj.202502590R
Int J Mol Sci. 2025 Nov 15. pii: 11052. [Epub ahead of print]26(22):

Mitochondria-Enriched Extracellular Vesicles (EVs) for Cardiac Bioenergetics Restoration: A Scoping Review of Preclinical Mechanisms and Source-Specific Strategies.

Dhienda C Shahannaz, Tadahisa Sugiura, Taizo Yoshida.

  Mitochondrial dysfunction is a pivotal contributor to cardiac disease progression, making it a critical target in regenerative interventions. Extracellular vesicles (EVs) have recently emerged as powerful mediators of mitochondrial transfer and cardiomyocyte repair. This review highlights recent advancements in EV bioengineering and their applications in cardiac mitochondrial rescue, with a particular focus on EVs derived from induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Drawing upon a growing body of preclinical evidence, we examine the mechanisms of mitochondrial content delivery, EV uptake dynamics, and comparative bioenergetic restoration outcomes across EV sources. Special emphasis is placed on therapeutic outcomes such as adenosine triphosphate (ATP) restoration, reactive oxygen species (ROS) modulation, and improvements in contractility and infarct size. The convergence of mitochondrial biology, stem cell-derived EV platforms, and engineering innovations positions mitochondria-enriched EVs as a promising non-cellular regenerative modality for cardiovascular disease.

Keywords:  cardiac regenerative therapy; cardiomyocyte repair; extracellular vesicles (EVs); heart failure; induced pluripotent stem cell (iPSCs); mitochondrial dysfunction; mitochondrial transfer; regenerative medicine; stem cell-derived exosomes; targeted organelle delivery

DOI:  https://doi.org/10.3390/ijms262211052
Cells. 2025 Nov 17. pii: 1801. [Epub ahead of print]14(22):

Distinct Neurodegenerative Pathways in Two NBIA Subtypes: Inflammatory Activation in C19orf12 but Not in PANK2 Mutation Carriers.

Marta Skowrońska, Agnieszka Cudna, Barbara Pakuła, Magdalena Lebiedzińska-Arciszewska, Justyna Janikiewicz, Aneta M Dobosz, Patrycja Jakubek-Olszewska, Agata Wydrych, Maciej Cwyl, Agnieszka Dobrzyń, Mariusz R Więckowski, Iwona Kurkowska-Jastrzębska.

   BACKGROUND: Biomarker analysis in neurodegeneration with brain iron accumulation (NBIA) can offer valuable insights into the disease's pathology and natural history.
METHODS: Twenty-five patients with C19orf12 mutations causing mitochondrial membrane protein-associated neurodegeneration (MPAN), 12 patients with PANK2 mutations causing pantothenate kinase-associated neurodegeneration (PKAN), and 30 age- and gender-matched controls were studied. Serum levels of MMP-9, S100B, ICAM-1, E- and P-selectins, total α-synuclein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Tau, ubiquitin-C-terminal hydrolase-L1 (UCH-L1), and brain-derived neurotrophic factor (BDNF) were measured. Clinical status was evaluated with dedicated rating scales.
RESULTS: Compared to the control group, MPAN patients had significantly higher serum levels of nearly all biomarkers, except BDNF. NfL, GFAP, and UCH-L1, were elevated by 5, 2, and 3.5 times, respectively. PKAN patients showed no significant differences in GFAP, UCH-L1, and S100B levels compared to controls. However, NfL and Tau levels were increased by 3 and 1.8 times, respectively. A correlation was observed between disease severity and levels of NfL, Tau, and UCH-L1 in MPAN, and GFAP, Tau, and UCH-L1 in PKAN.
CONCLUSIONS: Patients with MPAN and PKAN showed increased levels of neurodegeneration biomarkers. Elevated inflammation and blood-brain barrier dysfunction biomarkers were specific to MPAN patients.

Keywords:  MPAN; PKAN; biomarkers; neurodegeneration with brain iron accumulation

DOI:  https://doi.org/10.3390/cells14221801
Life (Basel). 2025 Nov 13. pii: 1744. [Epub ahead of print]15(11):

Mitochondrial DNA Deletions and Plasma GDF-15 Protein Levels Are Linked to Hormonal Dysregulation and Multi-Organ Involvement in Female Reproductive Endocrine Disorders.

Vera Varhegyi, Barnabas Banfi, Domonkos Trager, Dora Gerszi, Eszter Maria Horvath, Miklos Sipos, Nandor Acs, Maria Judit Molnar, Szabolcs Varbiro, Aniko Gal.

  Mitochondrial dysfunction contributes to female reproductive endocrine disorders and is frequently associated with multisystem symptoms. Insulin resistance (IR) is a common metabolic disorder strongly linked to polycystic ovary syndrome (PCOS), while premature ovarian insufficiency (POI) also impairs fertility. Mitochondrial DNA (mtDNA) deletions and the stress-responsive cytokine growth differentiation factor 15 (GDF-15) have recently emerged as complementary biomarkers of mitochondrial impairment. In this retrospective observational study, we examined reproductive hormones, plasma GDF-15, mtDNA deletions, and clinical symptoms in insulin-resistant women, including those with PCOS or POI. Eighty-one patients were divided into three subgroups: IR-only (n = 49), IR-PCOS (n = 19), and IR-POI (n = 13). IR was defined based on elevated insulin levels during oral glucose tolerance testing (>10 mU/L at 0 min, >50 mU/L at 60 min, >30 mU/L at 120 min) according to national gynecological endocrinology guidelines, acknowledging that IR is not universally accepted as a distinct clinical entity. POI was defined as reduced ovarian reserve before age 40 with anti-Müllerian hormone (AMH) <1.0 ng/mL. Clinical symptoms were assessed using a questionnaire, medical record, and physical examination. MtDNA deletions were detected by long-range PCR, and GDF-15 was measured by ELISA. Free thyroxine (T4) emerged as an independent predictor of GDF-15, suggesting that thyroid function modulates mitochondrial stress signaling in insulin-resistant women. MtDNA deletions and/or elevated GDF-15 correlated with endocrine, gastrointestinal, and neuropsychiatric symptoms, and reduced AMH/FSH ratios indicated impaired ovarian function. Cross-sectional analysis further revealed lower AMH and AMH/FSH ratios in older women with mtDNA deletions, consistent with a trend toward accelerated reproductive aging. Overall, these findings support the role of GDF-15 and mtDNA deletions as complementary biomarkers of mitonuclear stress, with potential relevance for both systemic and reproductive health.

Keywords:  GDF-15; PCOS; POI; insulin resistance; mitochondrial dysfunction; mtDNA deletion

DOI:  https://doi.org/10.3390/life15111744
J Neuroinflammation. 2025 Nov 25. 22(1): 279

Metabolic reprogramming and altered ATP content impair neuroprotective functions of microglia in β-glucocerebrosidase deficiency models.

Electra Brunialti, Alessandro Villa, Eva M Szego, Pietro La Vitola, Denise Drago, Radmila Pavlovic, Laura Fontana, Doga Tuna, Alessia Panzeri, Clara Meda, Christin Weissleder, Ornella Rondinone, Mattia Pitasi, Monica Miozzo, Michela Deleidi, Annapaola Andolfo, Donato A Di Monte, Paolo Ciana.



Keywords:  ATP; Energetic failure; Gaucher’s disease; Microglia; Neuroprotection; Parkinson’s disease

DOI:  https://doi.org/10.1186/s12974-025-03616-y
Kidney Int Rep. 2025 Nov;10(11): 3945-3957

Prenatal Diagnosis of COQ2 Variants in Suspected Coenzyme Q10 Deficiency.

Zhanqi Feng, Liangjie Guo, Yue Gao, Mengting Zhang, Xiuming Liu, Bing Kang, Mengyao Tan, Shixiu Liao, Hongdan Wang.

   Introduction: Primary coenzyme Q10 (CoQ10) deficiency is a rare mitochondrial disorder with multisystem involvement, often undiagnosed in prenatal stages because of phenotypic variability and ambiguous genetic findings. Here, we report a prenatal case of primary CoQ10 deficiency type 1 diagnosed using amniocentesis, identifying compound heterozygous COQ2 variants (a maternally inherited novel splice-site variant c.779-2A>G and paternally inherited c.973A>G) in a fetus exhibiting growth restriction and cardiac anomalies.
Methods: Through family-based whole-exome sequencing, we identified compound heterozygous COQ2 variants in a fetus with severe growth restriction. Pathogenicity was confirmed via minigene splicing assays and yeast complementation.
Results: Minigene splicing assays demonstrated that the c.779-2A>G splice-site variant induced complete exon 5 skipping, generating a frameshift truncation (p.Leu261Glnfs∗4) that abolished the polyprenyltransferase domain. Functional studies in coq2Δ yeast revealed that both alleles impaired respiratory growth, with the truncation variant (c.779-2A>G) showing complete loss of function, whereas the missense variant (c.973A>G) exhibited partial residual activity (OD600 = 0.52 vs. wild-type 0.59). Structural modeling of p.Thr325Ala highlighted destabilization of the substrate-binding pocket because of disrupted hydrogen bonds (Thr325- Gly322/His303).
Conclusion: To the best of our knowledge, this study provided the first experimental evidence for the hypomorphic nature of c.973A>G, observed in Asian cohorts with nephropathy but previously classified as a variant of uncertain significance. The variant has a minor allele frequency of 0.00071 in the gnomAD East Asian population, compared with < 0.00001 globally. This study expanded the screening spectrum of COQ2 and provided mechanistic insights into genotype-phenotype correlations in primary CoQ10 deficiency.

Keywords:  human COQ2 gene; prenatal diagnosis; primary coenzyme Q10 deficiency; yeast mutant complementation

DOI:  https://doi.org/10.1016/j.ekir.2025.08.023