bims-mitmed 2026-03-01 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–03–01
seventeen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.
Nutrient and endocrine factors affecting impaired growth in pediatric mitochondrial diseases.
Generative AI Accelerates Genotype-Phenotype Characterization of a 1600-Case Leigh Syndrome Virtual Cohort from Published Literature.
Muscle biopsy and mitochondrial disease criteria as diagnostic tools for paediatric patients presenting with neuromuscular phenotypes: highlighting the role of secondary mitochondrial dysfunction.
Mitochondrial Dysfunctions in Human Primary Coenzyme Q10 Deficiencies.
OPA1 Deficiency Impairs NGF Signaling and Drives Sympathetic Neurodegeneration.
Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.
Engineering Mitochondrial Biogenesis in iPSC-CMs: CRISPR-Guided Approaches for Advanced Cardiomyocyte Development.
Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
Mitochondria in Renal Ischemia-Reperfusion Injury: From Mechanisms to Therapeutics.
The Citric Acid Cycle Modulates Neurologic Health and Is a Therapeutic Target of Dietary and Genetic Modification in Metabolic Disease.
Targeting mitochondrial phosphatase PGAM5 alleviates ferroptosis and acute pancreatitis by upregulating NRF2-mediated FSP1 expression.
PRMT5 in mitochondria regulates mtDNA stability through TFAM arginine methylation.
From the energy factory to the intercellular communication medium: the emerging role of intercellular mitochondrial transfer and mitochondrial transplantation therapy in diabetes and diabetic complications.
PPARγ activation rescues oxidative stress-induced embryonic arrest by suppressing Wnt/β-catenin signaling via GSK3β upregulation.
VAMP7-dependent late endosomal secretion of ER and mitochondrial proteins impacts the tumor microenvironment and macrophage engagement.
The fetal frontier: A review of current and emerging fetal therapies for genetic diseases.

Nat Struct Mol Biol. 2026 Feb 27.

Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.

Lara Kroczek, Hendrik Nolte, Yvonne Lasarzewski, Ishita Agrawal, Thibaut Molinié, Daniel Curbelo Piñero, Kathrin Lemke, Elena Rugarli, Thomas Langer.

Mitochondria dynamically adapt to cellular stress to ensure cell survival. The stress-regulated mitochondrial peptidase OMA1 orchestrates these adaptive responses, which limit mitochondrial fusion and promote mitochondrial stress signaling and metabolic rewiring. Here, we show that cellular stress adaptation involves OMA1-mediated regulation of mitochondrial protein import and OXPHOS biogenesis. OMA1 cleaves the mitochondrial chaperone DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under conditions of mitochondrial dysfunction. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum, inducing an unfolded protein response. Our results demonstrate stress-dependent changes in mitochondrial protein import as part of the OMA1-mediated mitochondrial stress response and highlight the interdependence of proteostasis regulation between different organelles.

DOI: https://doi.org/10.1038/s41594-026-01756-0
Endocrinol Diabetes Metab Case Rep. 2026 Jan 01. pii: EDM250140. [Epub ahead of print]2026(1):

Nutrient and endocrine factors affecting impaired growth in pediatric mitochondrial diseases.

Hideaki Yagasaki, Hiromune Narusawa, Daisuke Watanabe, Fumikazu Sano, Kaoru Fujioka, Sonoko Mizorogi, Yoshimi Kaga, Takeshi Inukai.

   Summary: Mitochondrial diseases cause systemic failure of energy production and can manifest as various disorders of hormone production and secretion from endocrine organs. These effects can prevent normal growth in children, resulting in adults of short stature. We therefore explored the nutritional and endocrinological status of pediatric mitochondrial disease patients with impaired growth. Four Japanese patients with genetically diagnosed mitochondrial disease were studied (one male and three females, aged 4-22 years). The age of onset ranged from 0 months to 7 years, and the causal genes identified were mtDNA, PDHA1, and NARS2 (in two sibling patients). Two patients were diagnosed with small for gestational age at birth, and their current height standard deviation scores ranged from -1.9 SD to -6.4 SD. Mitochondrial diseases can present as impaired growth with dysfunction of various organs, depending on the causal gene and the degree of heteroplasmy. Our patients had demonstrated low T3 syndrome and reduced IGF1 levels, which appeared to be influenced by impaired nutritional status. These findings emphasize the need for careful monitoring of growth trajectories alongside nutritional and endocrine evaluations to improve clinical management.
Learning points: Mitochondrial diseases can disrupt endocrine function involving the GH-IGF1 axis and the thyroid and gonadal systems, leading to impaired growth during childhood. Patients with early-onset mitochondrial disease tend to experience severe symptoms and pronounced growth impairment. Children with mitochondrial diseases often show low IGF1 levels, low T3 syndrome, and delayed bone age, reflecting endocrine dysfunction commonly observed in chronic systemic diseases and the further influence of suboptimal nutritional status.

Keywords:  diabetes; impaired growth; insulin-like growth factor 1; mitochondria

DOI:  https://doi.org/10.1530/EDM-25-0140
Biology (Basel). 2026 Feb 14. pii: 334. [Epub ahead of print]15(4):

Generative AI Accelerates Genotype-Phenotype Characterization of a 1600-Case Leigh Syndrome Virtual Cohort from Published Literature.

Lishuang Shen.

  Leigh Syndrome Spectrum (LSS) is a rare and heterogeneous disease continuum with most published cohorts in small sizes that limit the statistical power. Large-scale meta-analyses with published case-level clinical data extracted from the literature are essential for robust population analysis but are hindered by the burden of manually standardizing the unstructured, heterogeneous, and sparse case-level data from the literature. We developed a novel workflow which is among the first to combine Generative AI (GenAI) with human-in-the-loop curation to overcome this barrier. This pipeline utilized Google's Gemini-2.5-pro and rapidly processed over 2300 cases from published case data tables in two weeks and achieved >90% accuracy in mapping raw clinical data to Human Phenotype Ontology (HPO) terms. This process rapidly yielded a harmonized LSS virtual cohort of 1679 data-rich cases, which is the largest LSS virtual cohort reported so far, and thus enables characterization of LSS phenotypic and genetic architectures, revealing that autosomal recessive (932 cases) and mitochondrial (752 cases) inheritance are the most common. The most frequently mutated genes were SURF1 (240 cases), MT-ATP6 (199), and MT-ND3 (183). HPO term consolidation identified common hallmark phenotypes, including lactic acidosis, hypotonia, bilateral basal ganglia lesions, and mitochondrial respiratory chain deficiency. The cohort's scale enabled large-scale survival analysis, revealing that defects in mitochondrial translation are associated with the poorest prognosis (84% mortality in this group) and early onset (0.23 years). Among the deceased group, patients with Complex V mutations were linked to a significantly shorter mean survival time (1.77 years) than those with Complex I (3.70 years) or IV (3.57 years) mutations. This GenAI-driven methodology establishes a scalable framework for rapidly creating analysis-ready virtual cohorts from heterogeneous literature and accelerating population-level study for rare diseases including Leigh Syndrome and other mitochondrial diseases.

Keywords:  Leigh Syndrome Spectrum (LSS); Leigh disease; generative AI (GenAI); human phenotype ontology (HPO); large language model; rare disease

DOI:  https://doi.org/10.3390/biology15040334
Neuromuscul Disord. 2026 Feb 06. pii: S0960-8966(26)00038-6. [Epub ahead of print]61 106370

Muscle biopsy and mitochondrial disease criteria as diagnostic tools for paediatric patients presenting with neuromuscular phenotypes: highlighting the role of secondary mitochondrial dysfunction.

Milla-Riikka Hautakangas, Tommi Niskanen, Päivi Vieira, Heli Helander, Anne M Portaankorva, Heikki Rantala, Reetta Hinttala, Johanna Uusimaa.

  This study evaluated the diagnostic utility of muscle biopsy and the performance of the Nijmegen and modified Walker criteria in a real-life paediatric cohort with neuromuscular symptoms. A retrospective review at Oulu University Hospital included 220 paediatric patients with unexplained neuromuscular symptoms who underwent muscle biopsy between 1990 and 2024. Clinical data were collected, and patients were classified using both criteria. A genetic diagnosis was confirmed in 58 patients (26 %): 12 with primary mitochondrial diseases (21 %), 17 with secondary mitochondrial dysfunction (29 %), and 29 with other neuromuscular disorders (50 %). OXPHOS activities were measured in 189 patients (86 %); 49 (26 %) showed decreased activity, including 13 with genetic confirmation. Electron microscopy (n=175) showed mitochondrial abnormalities in 49 patients (28 %); 75 % of these had mitochondrial disease. The modified Walker criteria outperformed the Nijmegen (sensitivity 75 % vs 50 %; specificity 100 % vs 98 %). Mean Nijmegen scores were significantly higher in primary mitochondrial disease (p<0.05), also compared with patients with secondary dysfunction. In conclusion, muscle biopsy and mitochondrial disease criteria remain valuable tools distinguishing primary mitochondrial diseases. This study highlights the role of secondary mitochondrial dysfunction in non-mitochondrial genetic conditions and metabolic diseases with undefined genetic aetiologies waiting to be identified in the future.

Keywords:  Encephalomyopathy; Mitochondrial disease criteria; Muscle biopsy; Neuromuscular symptoms; Secondary mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.nmd.2026.106370
Biomolecules. 2026 Feb 14. pii: 302. [Epub ahead of print]16(2):

Mitochondrial Dysfunctions in Human Primary Coenzyme Q10 Deficiencies.

Fanny Fontaine, Romain Pénicaud, Stéphane Allouche.

  Coenzyme Q10 (CoQ10) is an essential lipid-soluble molecule that plays a central role in mitochondrial energy production as a mobile electron carrier. In addition to its bioenergetic function, CoQ10 participates in antioxidant defense, redox homeostasis, lipid and nucleotide metabolism, and mitochondrial quality control. Primary CoQ10 deficiencies are rare inherited mitochondrial disorders caused by pathogenic variants in nuclear genes involved in CoQ10 biosynthesis. These defects lead to reduced CoQ10 levels and impaired mitochondrial functions. Clinically, primary CoQ10 deficiencies display remarkable phenotypic heterogeneity, ranging from isolated organ involvement, notably renal or cerebellar disease, to severe multisystemic disorders affecting the nervous system, skeletal muscle, heart, and other organs. Disease onset spans from the antenatal period to adulthood, and clinical severity varies widely, even among patients carrying variants in the same gene. This diversity cannot be fully explained by defective ATP production alone. Growing evidence indicates that disruption of non-bioenergetic functions of CoQ10, including oxidative stress regulation and CoQ-dependent metabolic pathways, contributes significantly to disease pathophysiology and tissue vulnerability. In this review, we summarize current knowledge on CoQ10 biology, biosynthesis, and the clinical spectrum of primary CoQ10 deficiencies, and we discuss emerging mechanisms linking CoQ10 depletion to mitochondrial dysfunctions and human diseases.

Keywords:  coenzyme Q10; metabolism; mitochondrial disorders; mitophagy; oxidative phosphorylation; oxidative stress; primary coenzyme Q10 deficiency

DOI:  https://doi.org/10.3390/biom16020302
JACC Basic Transl Sci. 2026 Feb;pii: S2452-302X(25)00413-9. [Epub ahead of print]11(2): 101460

OPA1 Deficiency Impairs NGF Signaling and Drives Sympathetic Neurodegeneration.

Marco Ronfini, Valentina Prando, Vittoria Di Mauro, Lolita Dokshokova, Erika Lazzeri, Irene Costantini, Lukas Alàn, Erwan Andre Riviere, Alex Incensi, Camilla Olianti, Chiara La Morgia, Rocco Liguori, Leonardo Sacconi, Vincenzo Donadio, Luca Scorrano, Valerio Carelli, Marco Mongillo, Tania Zaglia.

  Peripheral sympathetic neurodegeneration drives cardiac dysfunction in dominant optic atrophy, revealing a critical neuro-cardiac link. Optic atrophy factor-1 haploinsufficiency disrupts mitochondrial dynamics and neurotrophic signaling, causing targeted sympathetic denervation and arrhythmias. Restoring nerve growth factor transport and mitochondrial health in sympathetic neurons represents a promising therapeutic avenue for cardiac autonomic disorders. Future research must unravel mechanisms of neurocardiac crosstalk to develop precise interventions against neurogenic cardiac disease progression.

Keywords:  dominant optic atrophy; mitochondria; nerve growth factor; optic atrophy factor-1; sympathetic neurons

DOI:  https://doi.org/10.1016/j.jacbts.2025.101460
Autophagy Rep. 2026 ;5(1): 2629624

Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.

Mariana Joaquim, Maike F Dohrn, Arnaud Chevrollier, Mafalda Escobar-Henriques.

  Mitochondria are central hubs for cellular fitness, empowered by plastic remodeling of their shape, proteome composition, and/or metabolic state. MFN2 (mitofusin 2) mediates mitochondrial fusion and ensures adaptations in response to metabolic changes and stresses. Besides this canonical role, MFN2 serves as a communication hub with other organelles. It tethers mitochondria to the endoplasmic reticulum (ER), lipid droplets, and peroxisomes, regulating calcium buffering, apoptosis, lipid biosynthesis, and lipolysis. Dysfunctional MFN2 causes the hereditary neuropathy Charcot-Marie-Tooth type 2A (CMT2A) and is linked to several metabolic diseases. In a recent publication, we described another fusion-independent role of MFN2 in proteostasis and mitophagy. MFN2 binds the chaperone HSPA8/HSC70 (heat shock protein family A [Hsp70] member 8) and the proteasome, a key function in maintaining mitochondrial and cellular protein quality control, which appears to be lost in the context of CMT2A-associated MFN2 variants.

Keywords:  Charcot–Marie–Tooth type 2A (CMT2A); HSPA8/HSC70; MFN2; protein import; proteasome; VCP/p97; PINK1; apoptosis; mitophagy; proteostasis

DOI:  https://doi.org/10.1080/27694127.2026.2629624
J Cardiovasc Dev Dis. 2026 Feb 03. pii: 77. [Epub ahead of print]13(2):

Engineering Mitochondrial Biogenesis in iPSC-CMs: CRISPR-Guided Approaches for Advanced Cardiomyocyte Development.

Dhienda C Shahannaz, Tadahisa Sugiura, Brandon E Ferrell, Taizo Yoshida.

  Human iPSC-derived cardiomyocytes (iPSC-CMs) exhibit fetal-like mitochondrial networks and limited oxidative metabolism, constraining their translational utility. The key bottleneck is mitochondrial immaturity, resulting from blunted PGC-1α-NRF1/2-TFAM axis activation and insufficient nuclear-mitochondrial coordination, rather than sarcomeric or electrophysiological immaturity alone. This review synthesizes genome-guided interventions (CRISPRa and mtDNA editing) and complementary environmental strategies-including metabolic substrate switching, electromechanical stimulation, and extracellular vesicle (EV)-mediated mitochondrial transfer-to drive mitochondrial biogenesis and maturation in iPSC-CMs. We systematically reviewed studies (2005-2025) targeting (1) key regulators of mitochondrial biogenesis (PGC-1α, NRF1/2, TFAM), (2) CRISPR-based transcriptional activators/repressors and mtDNA editors (DdCBE, mitoTALENs), and (3) maturation approaches such as metabolic conditioning, electromechanical stimulation, 3D tissue culture, and EV-mediated mitochondrial transfer. CRISPRa-mediated activation of PGC-1α, NRF1, and GATA4, combined with mtDNA base editors, enhances mitochondrial mass and OXPHOS function, while integration with environmental maturation strategies further promotes adult-like phenotypes. Integrative approaches that combine genome-guided interventions (CRISPRa, mtDNA editing) with environmental maturation cues yield the most adult-like iPSC-CM phenotypes reported to date. CRISPR-guided mitochondrial biogenesis thus represents a frontier for producing metabolically competent, structurally mature iPSC-CMs for disease modeling and therapy. Remaining translational challenges include efficient mitochondrial delivery, metabolic homeostasis, and multi-omics validation. We propose standardized workflows to couple nuclear and mitochondrial editing with maturation strategies.

Keywords:  CRISPR activation (CRISPRa); PGC-1α signaling; cardiomyocyte maturation; extracellular vesicle therapy; iPSC-cardiomyocytes; metabolic conditioning in iPSC-CMs; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial genome editing; oxidative phosphorylation (OXPHOS)

DOI:  https://doi.org/10.3390/jcdd13020077
Nat Cell Biol. 2026 Feb 26.

Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.

Sandra Heinen, Vitasta Tiku, Alexander Grevel, Marie Hugenroth, Lars Ellenrieder, Isabelle Steymans, Mariya Licheva, Sara Bonini, Silke Oeljeklaus, Nicole Okon, Jessica Lambertz, Sylvia Poppe, Jiyao Song, Lars Fester, Chris Meisinger, Bettina Warscheid, Matthias Eckhardt, Nils Wiedemann, Dominic Winter, Claudine Kraft, Fabian den Brave, Maria Bohnert, Nikolaus Pfanner, Thomas Becker.

Mitochondria play central roles in the energetics and metabolism of eukaryotic cells. Their outer membrane is essential for protein transport, membrane dynamics, signalling and metabolic exchange with other cellular compartments. The mitochondrial import (MIM) complex functions as main translocase for importing the precursors of more than 90% of integral outer-membrane proteins. Here we report that the MIM complex performs a second major function in lipid-droplet homeostasis. Lipid droplets are crucial in cellular lipid metabolism and as storage organelles for neutral lipids. The lipid metabolism enzyme Ayr1 captures the MIM complex, promoting the formation of mitochondria-lipid droplet contact sites. MIM and Ayr1 enhance the lipid droplet number in cells. Ayr1 binds to MIM via its single hydrophobic segment in a substrate-mimicry mechanism but remains bound and is not released into the outer membrane. The functional diversity is mediated by different MIM complexes: MIM-Ayr1 for recruiting lipid droplets and MIM-preprotein for protein insertion into the outer membrane. Our work uncovers translocase capture as a mechanism for functional conversion of a membrane protein complex from protein insertion to lipid metabolism.

DOI: https://doi.org/10.1038/s41556-026-01890-3
Biomedicines. 2026 Jan 29. pii: 310. [Epub ahead of print]14(2):

Mitochondria in Renal Ischemia-Reperfusion Injury: From Mechanisms to Therapeutics.

Yijun Pan, Jiefu Zhu.

  Renal ischemia-reperfusion injury (IRI) is a leading trigger of acute kidney injury (AKI), a syndrome with high incidence and mortality worldwide. The kidney is among the most energy-demanding organs; its mitochondrial content is second only to the heart, rendering renal function highly contingent on mitochondrial integrity. Accumulating evidence places mitochondria at the center of IRI pathogenesis. During ischemia, ATP depletion, ionic disequilibrium, and Ca2+ overload set the stage for injury; upon reperfusion, a burst of mitochondrial reactive oxygen species (mtROS), collapse of the mitochondrial membrane potential (ΔΨm), aberrant opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA (mtDNA) damage, and release of mitochondrial damage-associated molecular patterns (mtDAMPs) further amplify inflammation and drive regulated cell-death programs. In recent years, the centrality of mitochondrial bioenergetics, quality control, and immune signaling in IRI-AKI has been increasingly recognized. Building on advances from the past five years, this review synthesizes mechanistic insights into mitochondrial dysfunction in renal IRI and surveys mitochondria-targeted therapeutic strategies-including antioxidant defenses, reinforcement of mitochondrial quality control (biogenesis, dynamics, mitophagy), and modulation of mtDAMP sensing-with the aim of informing future translational efforts in AKI.

Keywords:  AKI; antioxidant defenses; mitochondria; mitochondria-targeted therapy; mitochondrial DNA; mitochondrial quality control; mtDAMPs; renal ischemia–reperfusion injury

DOI:  https://doi.org/10.3390/biomedicines14020310
Genes (Basel). 2026 Feb 04. pii: 192. [Epub ahead of print]17(2):

The Citric Acid Cycle Modulates Neurologic Health and Is a Therapeutic Target of Dietary and Genetic Modification in Metabolic Disease.

Keri J Fogle, Sarah K Lindley, Sidney L Satterfield, Beakal A Amsalu, Joseph R Figura, Samantha L Eicher, Luke A Scherz, Michael J Palladino.

  Background/Objectives: Primary metabolic diseases including mitochondrial encephalomyopathies (ME), glycolytic enzymopathies, and disorders of lipid and amino acid metabolism can manifest with severe neurological and neuromuscular symptoms. Conversely, it is increasingly appreciated that primary neurodegenerative diseases can have metabolic etiology and pathophysiology. Pharmacological treatments have limited benefit for these classes of diseases, but dietary therapy is increasingly recognized as a tool for bolstering metabolic processes that can ameliorate neurological symptoms. The ketogenic diet is the best-established example, having long been used as a therapy for epilepsy. Replenishing metabolic intermediates (anaplerosis) especially substrates of the citric acid cycle (CAC) is currently being explored, with ongoing clinical trials of simple metabolic intermediates such as oxaloacetate or NAD+ to treat neurodegenerative diseases. We have shown ketogenic and anaplerotic therapies to be effective in a Drosophila model of ME; however, the full therapeutic potential and role of the CAC in neuronal health is still not well understood. Methods: Here, we have used genetic, behavioral, and dietary approaches to elucidate critical links between the CAC and neurological function. Results: We have found that stimulating the CAC can improve and sustain neurological health in the face of severe metabolic disease, and that its functions include a previously unrecognized role in maintaining normal circadian rhythms, whose disruption is often an early indicator or complicating factor in neurological and neurodegenerative disease. We investigated the hypothesis that the production of GTP by the CAC may be an important mechanistic contributor to the role of the CAC in neurological health and disease, and may underlie its therapeutic potential. Conclusions: Overall, our findings expand our understanding of the role of the CAC in neurological health and disease, support its development as a therapeutic target, and provide a foundation for further studies investigating the intersection between neurological disease and metabolic function.

Keywords:  Leigh Syndrome; anaplerosis; circadian rhythms; citric acid cycle; genetics; ketogenic diet; mitochondrial encephalomyopathy; nucleoside diphosphate kinase

DOI:  https://doi.org/10.3390/genes17020192
Cell Death Dis. 2026 Feb 21.

Targeting mitochondrial phosphatase PGAM5 alleviates ferroptosis and acute pancreatitis by upregulating NRF2-mediated FSP1 expression.

Shuang Ma, Jianhua Qin, Jing Luan, Guoyan Hou, Jiyuan He, Minghui Gao.

Ferroptosis is a regulated necrosis that is driven by iron-dependent lipid peroxidation. Phosphoglycerate mutase 5 (PGAM5), as a mitochondrial signaling hub, modulates mitochondrial dynamics, senses mitochondrial stress, and regulates the anti-oxidative response. However, the function of PGAM5 in ferroptosis remains elusive. Here, we discovered that PGAM5 emerges as a critical regulator of ferroptosis, with both genetic deletion and overexpression conferring protection against ferroptosis by upregulating nuclear factor erythroid 2-related factor 2 (NRF2) mediated ferroptosis suppressor protein 1 (FSP1) expression. On the one hand, dyregulation of PGAM5 upregulates NRF2 expression transcriptionally and inhibits its polyubiquitination. On the other hand, modulating the expression of PGAM5 results in energy stress ([AMP + ADP]/[ATP] ratio increase) and AMP-activated protein kinase (AMPK) activation. AMPK-dependent phosphorylation of NRF2 drives its nuclear accumulation, where it transcriptionally upregulates FSP1 to promote cell survival. Furthermore, pharmacological inhibition of PGAM5 attenuates arginine-induced acute pancreatitis, highlighting its therapeutic potential. Our findings establish PGAM5 as a central node in ferroptosis regulation and implicate its pathogenic role in acute pancreatitis.The molecular mechanism of alleviation of ferroptosis by dysregulation of PGAM5.

DOI: https://doi.org/10.1038/s41419-026-08484-9
Nat Commun. 2026 Feb 23.

PRMT5 in mitochondria regulates mtDNA stability through TFAM arginine methylation.

Sangheeta Bhattacharjee, Sayan Das, Banhi Chowdhury, Benu Brata Das.

Protein arginine methyltransferase 5 (PRMT5) catalyzes arginine methylation and regulates cellular functions such as proliferation, RNA splicing, and nuclear DNA damage response. This study uncovers that a fraction of nuclear-encoded PRMT5 localizes to the mitochondria, which is critical for maintaining mitochondrial DNA (mtDNA) homeostasis. PRMT5 knockout (PRMT5-/-) cells had reduced nucleoid counts, diminished mtDNA copy numbers, disrupted the balance of the mitochondrial fission-fusion cycle, impaired mitochondrial plasticity, and nucleoid trafficking. PRMT5-/- cells are hypersensitive to mtDNA-damaging agents, exhibit reduced mitochondrial transcripts, oxidative phosphorylation, and respiratory capacity that triggers cell death. We identify TFAM as a previously unrecognized interacting partner of PRMT5, which catalyzes symmetric dimethylation of TFAM at R82 residue, which is crucial for mtDNA binding and protection. Defective R82-methylation destabilizes TFAM, which is then degraded by LonP1. Together, we establish that PRMT5 is a mitochondrial enzyme and a key regulator of TFAM in mtDNA maintenance.

DOI: https://doi.org/10.1038/s41467-026-69676-7
J Transl Med. 2026 Feb 25.

From the energy factory to the intercellular communication medium: the emerging role of intercellular mitochondrial transfer and mitochondrial transplantation therapy in diabetes and diabetic complications.

Dongze Li, Xiaolan Liu, Li Zhang, Qiming Gong, Wei Huang, Yong Xu.



Keywords:  Diabetes; Diabetic complications; Mitochondrial dysfunction; Mitochondrial transfer; Mitochondrial transplantation

DOI:  https://doi.org/10.1186/s12967-026-07868-x
iScience. 2026 Mar 20. 29(3): 114870

PPARγ activation rescues oxidative stress-induced embryonic arrest by suppressing Wnt/β-catenin signaling via GSK3β upregulation.

Lihong Liu, Siyao Ha, Hui Chen, MingQing Li, Zhiling Li.

  Excessive reactive oxygen species (ROS) during assisted reproductive technology (ART) impairs embryonic development, yet the intrinsic molecular mechanisms remain inadequately understood. Through transcriptomic profiling (Drug-seq) of oxidatively stressed mouse embryos, we identified peroxisome proliferator-activated receptor gamma (PPARγ) as a critical regulator whose essential upregulation during zygotic genome activation (ZGA) is suppressed. Functional studies demonstrated that the pharmacological activation of PPARγ via the agonist GW1929 robustly rescued developmental arrest by scavenging ROS, restoring mitochondrial function, and maintaining metabolic homeostasis. Mechanistically, we demonstrate that PPARγ activation transcriptionally upregulates GSK3β, which in turn suppresses oxidative stress-induced aberrant Wnt/β-catenin signaling. Our findings establish PPARγ as a central guardian of embryonic redox and metabolic homeostasis, and propose PPARγ agonism as a potential strategy to improve ART outcomes by counteracting oxidative injury.

Keywords:  Biological sciences; Developmental biology; Developmental genetics

DOI:  https://doi.org/10.1016/j.isci.2026.114870
Nat Commun. 2026 Feb 21.

VAMP7-dependent late endosomal secretion of ER and mitochondrial proteins impacts the tumor microenvironment and macrophage engagement.

Somya Vats, Pedro Dionisio, Quentin Lemercier, Raphael Pineau, Ludivine Therreau, Joanna Lipecka, Béatrice Cholley, Jean-Baptiste Moog, Jose Wojnacki, Céline Keime, Diana Zala, Philippe Bun, Sofia Freire, Neuza Domingues, Lydia Danglot, Ida Chiara Guerrera, Cédric Delevoye, Eric Chevet, Nuno Raimundo, Thierry Galli.

Late endosomal secretion is an unconventional secretion mechanism that depends on the SNARE protein VAMP7. We previously showed that VAMP7 mediates the secretion of the ER protein Reticulon3. However, the functional relevance and molecular mechanism of this secretory pathway remain unclear. Here, we show that VAMP7 knockout cells exhibit impaired secretion of ER- and mitochondrial-derived proteins and signs of ER and mitochondrial stress. In addition, pharmacological induction of organellar stress enhances the VAMP7-dependent secretion. We assess the pathophysiological significance of this mechanism using a preclinical glioblastoma model. VAMP7 knockout glioblastoma cells implanted in male rat brain develop into more necrotic tumors with reduced macrophage infiltration compared to controls, suggesting that VAMP7-dependent late endosomal secretion contributes to the tumor microenvironment and affects macrophage infiltration. Together, our results support a model in which late endosomal secretion functions as an organelle quality-control and stress-communication mechanism, with particular relevance to cancer.

DOI: https://doi.org/10.1038/s41467-026-69900-4
Semin Pediatr Surg. 2026 Feb 10. pii: S1055-8586(26)00005-3. [Epub ahead of print] 151583

The fetal frontier: A review of current and emerging fetal therapies for genetic diseases.

Colton G Brown, Marissa Ray, Marco Carpenter, Braxton Forde, Tarun Subramanian, Haley Temple, Shivendra Tenguria, Laura Galganski.

  Pivotal advancements in diagnostics have greatly improved early detection of disease in the fetus. Rapid diagnosis of prenatal disease, including many aneuploidies and single-gene disorders, is now possible. These capabilities present an opportunity for earlier interventions and involvement of multidisciplinary care for infants discovered to have genetic disorders. While advancements continue to be made surgically addressing anatomic pathologies, more recently, the scope of fetal medicine has expanded to include the treatment of genetic disease. This unique and growing group of conditions with potential prenatal therapeutic targets spans broadly to include inborn errors of metabolism, neurodegenerative disorders, hematologic conditions, and errors in hormone biosynthesis. Because many of these hereditary conditions begin exerting deleterious effects before birth, prenatal therapies are critical to minimize or potentially avoid postnatal consequences. Fetal treatments can leverage the benefits of early human development such as a selectively permissive blood-brain barrier and a naive immune system. These factors, along with a favorable vector-to-tissue mass ratio in the fetus, create ideal treatment conditions that are not present after birth. Together, improved prenatal diagnostics and safe minimally invasive approaches for the delivery of therapies in utero have opened a window to what was previously an inaccessible population: the fetal patient. This review summarizes current clinical strategies and emerging investigational approaches, including enzyme replacement, protein therapy, stem cell transplantation, and gene-targeted interventions.

Keywords:  Fetal surgery; Fetal therapy; Gene therapy; Genetic disorders

DOI:  https://doi.org/10.1016/j.sempedsurg.2026.151583