bims-mitmed 2026-01-25 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–01–25
twenty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.
C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
NDUFS4, a mitochondrial complex I subunit, is essential for T-cell metabolic fitness and immune function.
Exploring Outcome Measures for Mitochondrial Myopathies; Insights From a Longitudinal Study on TK2 Deficiency.
Acetyl-CoA as a metabolic switch for selective mitophagy.
Mitochondrial Transplantation as a Therapeutic Strategy for Inherited Mitochondrial Diseases.
TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and Causal Perspectives.
Roles of DRP1 and the fission protein interactome as regulators of cellular stability and sarcopenia in skeletal muscle aging.
Ultrasound-assisted gene therapy mitigates Leigh syndrome pathology.
Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.
Dietary Protein Restriction Ameliorates Cardiac Inflammaging via AMPK-ULK1-Mediated Mitochondrial Quality Control.
Loss of Fatty Acid Oxidation by Neural Stem and Progenitor Cells Increases Proliferation but Does Not Improve Long-Term Neurogenesis After Mild Traumatic Brain Injury.
Deficiency of Microglial-Derived Spp1 Exacerbates Age-Related Memory Decline by Impairing Mitochondrial Complex I Function.
Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice.
Mitochondrial DNA is an important signaling molecule in cardiovascular aging and pathophysiology.
Single-Cell Mitochondrial Lineage Tracing Decodes Fate Decision and Spatial Clonal Architecture in Human Hematopoietic Organoids.
CRISPR/Cas9-mediated SLC2A1 gene knockout changes in energy metabolism and cellular behavior in human trophoblasts.
ATF4 regulates mitochondrial dysfunction and mitophagy, contributing to corneal endothelial apoptosis.
Leber Hereditary Optic Neuropathy-Associated Novel Mutation in MT-RNR2 Gene: A Case Report.
Successful treatment of neonatal COQ2 deficiency with 4-hydroxybenzoic acid.
Bioactives and exercise synergize to modulate AMPK and inflammation.
Hyperactivation of mTORC1 blocks stem cell fate transitions through TFE3-NuRD association.

JCI Insight. 2026 Jan 23. pii: e181812. [Epub ahead of print]11(2):

NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.

Joy Richard, Giulia Lizzo, Noélie Rochat, Adrien Jouary, Pedro Tm Silva, Alice Parisi, Stefan Christen, Sofia Moco, Michael B Orger, Philipp Gut.

  Mitochondria-derived acyl-coenzyme A (acyl-CoA) species chemically modify proteins, causing damage when acylation reactions are not adequately detoxified by enzymatic removal or protein turnover. Defects in genes encoding the mitochondrial respiratory complex and TCA cycle enzymes have been shown to increase acyl-CoA levels due to reduced enzymatic flux and result in proteome-wide hyperacylation. How pathologically elevated acyl-CoA levels contribute to bioenergetics failure in mitochondrial diseases is not well understood. Here, we demonstrate that bulk succinylation from succinyl-CoA excess consumes the enzymatic cofactor NAD+ and propagates mitochondrial respiratory defects in a zebrafish model of succinyl-CoA ligase deficiency, a childhood-onset encephalomyopathy. To explore this mechanism as a therapeutic target, we developed a workflow to monitor behavioral defects in sucla2-/- zebrafish and show that hypersuccinylation is associated with reduced locomotor behavior and impaired ability to execute food hunting patterns. Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2-/- zebrafish. Mechanistically, nicotinamide and nicotinamide riboside require the NAD+-dependent desuccinylase Sirt5 to enhance oxidative metabolism and nitrogen elimination through the urea cycle. Collectively, NAD+ supplementation activates Sirt5 to protect against damage to mitochondria and locomotor circuits caused by protein succinylation.

Keywords:  Cell biology; Genetic diseases; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.181812
Autophagy. 2026 Jan 22.

C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.

Jianshuang Li, Wenjun Wang, Li He, Qinghua Zhou.

  Mitochondria maintain homeostasis through dynamic remodeling and stress-responsive pathways, including the formation of specialized subdomains. Peripheral mitochondrial fission generates small MTFP1-enriched mitochondria (SMEM), which encapsulate damaged mtDNA and facilitate its macroautophagic/autophagic degradation. However, the underlying mechanism governing SMEM biogenesis remains unclear. In our recent study, we identified C3orf33/CG30159/MISO as a conserved regulator of mitochondrial dynamics and stress-induced subdomain formation in Drosophila and mammalian cells. C3orf33/MISO is an integral inner mitochondrial membrane (IMM) protein that assembles into discrete subdomains, which we confirm as small MTFP1-enriched mitochondria (SMEM). Mechanistically, C3orf33/MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway while suppressing fusion via OPA1 exclusion. Under basal conditions, MISO is rapidly turned over and contributes to mitochondrial morphology maintenance. Upon specific IMM stresses (e.g. mtDNA damage, OXPHOS dysfunction, cristae disruption), C3orf33/MISO is stabilized, thereby initiating SMEM assembly. These SMEM compartments function as stress-responsive hubs that spatially coordinate IMM reorganization and target damaged mtDNA to the periphery for lysosome-mediated clearance via mitophagy. Together, we address these fundamental gaps by identifying C3orf33/MISO as the key protein that controls SMEM formation to preserve mitochondrial homeostasis under stress.

Keywords:  Homeostasis; MISO; SMEM; mitochondrial subdomains; mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2621110
Front Immunol. 2025 ;16 1734203

NDUFS4, a mitochondrial complex I subunit, is essential for T-cell metabolic fitness and immune function.

Oded Shamriz, Zahala Bar-On, Omri Yosef, Leonor Cohen-Daniel, Ayelet Sheer, Or Reuven, Wajeeh Salaymeh, Amijai Saragovi, Raz Somech, Atar Lev, Hagar Mor-Shaked, Yuval Tal, Aviva Fattal-Valevski, Simon Edvardson, Michael Berger.

   Introduction: Mitochondrial metabolism is essential for T-cell function, but the roles of individual electron transport chain (ETC) components are unclear. Here, we aimed to explore the role of mitochondrial complex I (CI) subunit NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (NDUFS4) in T-cell metabolic fitness and immunity.
Methods: We used a T cell-specific Ndufs4 knockout mouse model to find that NDUFS4 deficiency disrupts CI function, leading to metabolic and redox imbalances. Additionally, T cells from a patient with Leigh syndrome induced by NDUFS4 loss-of-function were analyzed.
Results: Ndufs4-deficient T cells exhibit impaired OXPHOS, reduced respiratory capacity, and increased glycolysis, accompanied by reactive oxygen species (ROS) accumulation and defective TCR-driven activation, including reduced proliferation and cytokine production. In vivo, Ndufs4(-/-) mice show T-cell lymphopenia and impaired humoral and cytotoxic immunity. Importantly, T cells from a single Leigh syndrome patient with an NDUFS4 loss-of-function variant showed similar defects, including impaired activation and proliferation.
Discussion: These findings highlight the importance of NDUFS4 for human immunity and establish a mechanistic link between complex I dysfunction and T-cell immunodeficiency. Our results identify NDUFS4 as a key regulator connecting mitochondrial integrity to adaptive immune function.

Keywords:  NDUFS4; NDUFS4 knockout mice; T cells; leigh syndrome (LS); mitochondria

DOI:  https://doi.org/10.3389/fimmu.2025.1734203
J Inherit Metab Dis. 2026 Jan;49(1): e70147

Exploring Outcome Measures for Mitochondrial Myopathies; Insights From a Longitudinal Study on TK2 Deficiency.

Paloma Martín-Jimenez, Laura Bermejo-Guerrero, Luz Edith Ochoa, María Navarro-Riquelme, Rocío Garrido-Moraga, Aurelio Hernández-Laín, Ana Hernández-Voth, Adrián González Quintana, Ana Bermejo-Moriñigo, Violeta González-Méndez, Cristina Martín-Arriscado Arroba, Dimitrii Smirnov, Nikita Konstantinovskiy, Joaquín Arenas, Miguel Ángel Martin, Alberto Blázquez, Cristina Domínguez-González.

  Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial myopathy with variable presentations, including late-onset forms beginning after age 12. Unlike early-onset disease, the natural history of late-onset TK2d remains poorly defined. We conducted a prospective, single-centre natural history study of 11 untreated patients with late-onset TK2d over 24 months. The median age at symptom onset was 27.2 years. Clinical phenotypes included progressive myopathy (n = 7), chronic progressive external ophthalmoplegia plus (n = 2), and exercise intolerance (n = 2). Most patients (72%) required non-invasive ventilation, and 70% showed axonal polyneuropathy. All patients carried biallelic pathogenic TK2 variants, with p.Lys202del being the most common (13/22 alleles). Muscle biopsies demonstrated mitochondrial DNA depletion and multiple deletions, and muscle MRI consistently showed selective involvement of the sartorius, gracilis and gluteus maximus, whose fat fraction correlated with motor impairment. Functional assessments revealed a mean forced vital capacity of 70.4%, an NSAA score of 25.9, a six-minute walk distance of 479.5 m, and a 100-m run time of 60.5 s. Serum GDF15 levels were elevated (median 2747.5 pg/mL) and significantly correlated with motor and respiratory function. Over 2 years, patients showed measurable clinical deterioration, with declines in NSAA (-2.65 points), FVC (-9.11%), and worsening 100-meter run times (+6 s). This study provides the first prospective longitudinal characterization of late-onset TK2d and identifies clinically relevant, quantifiable outcomes that may inform future therapeutic trials targeting this underrepresented patient population. Moreover, these results are also relevant for the design of clinical trials in other mitochondrial myopathies.

Keywords:  GDF15; TK2 deficiency; biomarkers; late‐onset; mitochondrial myopathy; natural history

DOI:  https://doi.org/10.1002/jimd.70147
Autophagy. 2026 Feb;22(2): 235-237

Acetyl-CoA as a metabolic switch for selective mitophagy.

Daolin Tang, Rui Kang, Daniel J Klionsky.

  A recent study published in Nature by Zhang et al. reported that cytosolic acetyl-CoA functions as a signaling metabolite that regulates NLRX1-dependent mitophagy during nutrient stress. This discovery reveals a metabolic checkpoint for mitochondrial quality control and provides new insights into KRAS inhibitor resistance.

Keywords:  Acetyl-CoA; KRAS inhibitor; NLRX1; metabolic signaling; mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2593032
Adv Sci (Weinh). 2026 Jan 22. e23368

Mitochondrial Transplantation as a Therapeutic Strategy for Inherited Mitochondrial Diseases.

Parmeshar Singh, Amir Tahavvori, Cyrus E Kuschner, Blanca B Espin, Jacob Kazmi, Sofhia V Ramos, Tai Yin, Kei Hayashida, Kanako Ito-Hagiwara, Yusuke Endo, Keitaro Yoshioka, Jun Hagiwara, Avijot Sohi, Alisha Oropallo, Ghania Haddad, Timmy Li, Lance B Becker, Junhwan Kim.

  Mitochondria are essential organelles responsible for cellular energy production and diverse metabolic processes. Mitochondrial dysfunction is implicated in a wide range of diseases. Specifically, genetic mitochondrial diseases, arising from mutations in mitochondrial or nuclear DNA, lead to significant mitochondrial deficits, which result in debilitating and often life-threatening symptoms. Conventional treatments frequently fail to address these underlying mitochondrial defects, leaving few therapeutic options. Mitochondrial transplantation (MTx), an emerging therapeutic approach involving the delivery of healthy exogenous mitochondria to target cells, has demonstrated beneficial effects in various mitochondria-mediated diseases in both preclinical and early clinical studies. However, its application to inherited mitochondrial disorders remains largely unexplored and raises important questions about the need for repeated or continuous administration to sustain therapeutic effects. This review systematically examines the potential of MTx for inherited mitochondrial disorders by classifying these diseases by mitochondrial and nuclear DNA origin, critically assessing MTx evidence and mechanisms, and identifying unique translational requirements for chronic inherited disorders. While significant challenges remain, MTx represents a promising approach to directly address mitochondrial dysfunction in these life-threatening conditions with limited therapeutic alternatives.

Keywords:  chronic diseases; genetic diseases; mitochondrial transplantation; therapeutics

DOI:  https://doi.org/10.1002/advs.202523368
FASEB J. 2026 Jan 31. 40(2): e71467

TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and Causal Perspectives.

Yuxuan Zhang, Ximeng Wang, Dachuan Li, Xiao Lu, Zhaoyang Gong, Zhidi Lin, Hanqiu Sun, Hongli Wang, Zian Lu, Xiaosheng Ma, Guangyu Xu, Jianyuan Jiang.

  The polarization state of microglia exerts an influence on neuroinflammation and neural tissue repair after injury. Modulating microglial polarization is emerging as a potential therapeutic strategy for various types of neural injuries and neurodegenerative diseases. However, the causal relationship between microglial polarization and mitochondrial dynamics, which include mitochondrial fusion and fission, remains to be fully clarified. Our study demonstrates that mitochondrial fusion promoter M1 promotes mitochondrial fusion in mouse microglial cells, leading to reduced glycolysis and increased fatty acid oxidation, and this metabolic reprogramming impacts microglial polarization. Additionally, in both cellular and animal experiments, it was observed that knocking down mitochondrial transcription factor A (TFAM) results in increased mitochondrial fission, decreased fatty acid β-oxidation, enhanced glycolysis, and promotes the polarization of microglia toward the pro-inflammatory M1 phenotype. In conclusion, our study has, for the first time, provided evidence that TFAM may play a role in the regulation of mitochondrial dynamics. Furthermore, we provide a detailed elucidation of the chronological sequence and underlying causal relationships among mitochondrial dynamics, mitochondrial metabolic reprogramming, and microglial polarization. These findings offer novel targets and strategies for the treatment of various neural injuries and neurodegenerative diseases.

Keywords:  TFAM; cell polarization; fatty acid oxidation; glycolysis; metabolism; microglia; mitochondria

DOI:  https://doi.org/10.1096/fj.202503182RR
Aging Adv. 2025 Dec 18.

Roles of DRP1 and the fission protein interactome as regulators of cellular stability and sarcopenia in skeletal muscle aging.

C Nivedya, Prasanna Venkhatesh, Benjamin I Rodriguez, Han Le, Jeremiah Afolabi, Andrea Marshall, Kit Neikirk, Sepiso K Masenga, Muhammad Aftab, Leo Jake Kazma, Prasanna Katti, Antentor Hinton.

  Mitochondrial function is crucial in regulating cellular activity and determining cell fate. The replication and transcription of mitochondrial DNA are essential for maintaining mitochondrial integrity. These processes are governed by mitochondrial fission and fusion, which play a vital role in energy distribution, quality control, and metabolic regulation. Mitochondrial fission relies on the coordinated actions of mitochondria-endoplasmic reticulum contact sites, actin filaments, and dynamin-related protein 1, which collectively mediate mitochondrial constriction and fission. This interplay is fundamental to mitochondrial homeostasis and, critically, to the functionality of skeletal muscle. In this review, we explore the complex interactions among dynamin-related protein 1, mitochondria-endoplasmic reticulum contact sites, and actin and their significance for skeletal muscle function. Additionally, we discuss potential strategies to preserve these interactions, supporting optimal muscle performance in skeletal muscle aging. This review provides key insights and outlines future research directions to advance our understanding of this essential yet widely studied relationship.

Keywords:  dynamin-related protein 1 (DRP1); exercise interventions; fission and fusion; mitochondria quality control; mitochondrial dynamics; mitochondria–endoplasmic reticulum contact sites (MERCs); mitophagy; posttranslational modifications; sarcopenia; skeletal muscle aging

DOI:  https://doi.org/10.4103/agingadv.agingadv-d-25-00013
Brain. 2026 Jan 23. pii: awag026. [Epub ahead of print]

Ultrasound-assisted gene therapy mitigates Leigh syndrome pathology.

Mathilde Faideau, Romain Clément, Sébastien Rigollet, Giorgia Benegiamo, Cassandra Cresson, Béatrice Blot, Robin Reynaud-Dulaurier, Sara Yjjou, Fanny Aprahamian, Sylvère Durand, Anthony Delalande, Emmanuel L Barbier, Vasile Stupar, Johan Auwerx, Michael Decressac.

  Leigh syndrome (LS) is a fatal neurometabolic disease caused by mutations in genes involved in mitochondrial energy harvesting. While there is currently no cure for this disease, pre-clinical studies showed that gene therapy can afford a therapeutic benefit in a relevant model of LS, the Ndufs4-KO mouse. However, similar results need to be obtained using methods that can be translated in patients. Here, we combined two tools that are approved for clinical interventions. We used low-intensity focused ultrasound (FUS) to transiently permeabilize the blood-brain barrier and thereby facilitate the passage of an AAV9 vector. This approach resulted in transgene expression in the brain and peripheral organs. When applied to one-month old Ndufs4-KO mice, this gene replacement strategy significantly extended the survival of the animals and ameliorated brain and cardiac function. These improvements were associated with the restoration of protein expression and mitochondrial function. These findings support the potential of combining FUS with AAV-mediated gene delivery to treat LS and they warrant further clinical translation. This study also provides the first evidence that ultrasound-assisted gene replacement can exert a therapeutic effect in a condition affecting the central nervous system.

Keywords:  AAV vector; focused ultrasound; gene replacement; mitochondrial disease

DOI:  https://doi.org/10.1093/brain/awag026
Cardiovasc Res. 2026 Jan 20. pii: cvag011. [Epub ahead of print]

Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.

Colleen S Stein, Xiaoming Zhang, Nathan H Witmer, Edward Ross Pennington, Scott Hahn, Adam C Straub, Saame Raza Shaikh, Ryan L Boudreau.

   AIMS: We and others discovered a highly conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln strongly binds cardiolipin (CL), increases mitochondrial respiration and Ca2+ retention capacities, and reduces reactive oxygen species (ROS). Here we extend our observation of Mtln-CL binding and examine Mtln influence on cristae structure and mitochondrial membrane integrity during stress.
METHODS AND RESULTS: We demonstrate that mitochondria from constitutive- and inducible Mtln-knockout (KO) mice are susceptible to membrane freeze-damage and that this can be rescued by acute Mtln re-expression. In mitochondrial-simulated lipid monolayers, we show that synthetic Mtln decreases lipid packing and monolayer elasticity. Lipidomics revealed that Mtln-KO heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodeling. Lastly, we demonstrate that Mtln-KO mice suffer worse myocardial ischemia-reperfusion injury, hinting at a translationally relevant role for Mtln in cardioprotection.
CONCLUSION: Our work supports a model in which Mtln binds cardiolipin and stabilizes mitochondrial membranes to broadly influence diverse mitochondrial functions, including lipid metabolism, while also protecting against stress.

Keywords:  Cyb5r3; cardiolipin; cardioprotection; cristae; docosahexaenoic acid; ischemia-reperfusion; mitochondria; monolysocardiolipin; permeability transition; triglycerides

DOI:  https://doi.org/10.1093/cvr/cvag011
Aging Cell. 2026 Feb;25(2): e70386

Dietary Protein Restriction Ameliorates Cardiac Inflammaging via AMPK-ULK1-Mediated Mitochondrial Quality Control.

Wagner S Dantas, Elizabeth R M Zunica, Elizabeth C Heintz, Charles L Hoppel, Cristal M Hill, Christopher D Morrison, Christopher L Axelrod, Gangarao Davuluri, John P Kirwan.

  Calorie restriction (CR) is a robust intervention for improving metabolic health and delaying obesity and age-related diseases, yet its translational utility is limited by adherence challenges and diminished effectiveness later in life. Dietary protein restriction (DPR), which reduces dietary protein without decreasing total caloric intake, has emerged as a promising alternative, yet its cardioprotective potential in the context of obesity and aging remains poorly understood. Here, we demonstrate that DPR mitigates obesity-induced cardiac remodeling and inflammaging by activating the AMPK-ULK1 signaling axis and enhancing mitochondrial quality control. In middle-aged male mice with high-fat diet-induced obesity, 4 months of DPR attenuated cardiac hypertrophy and normalized heart failure markers, independently of FGF21 signaling. Transcriptomic and protein analyses revealed that DPR suppressed the activation of the cGAS-STING pathway, reduced mitochondrial DNA release into the cytosol, and blunted expression of pro-inflammatory mediators, including IRF3 and IFN-γ. DPR also restored mitochondrial dynamics, enhanced mitophagy, and maintained ATP content despite reduced respiratory capacity. Mechanistically, DPR increased AMPK-dependent ULK1 phosphorylation while suppressing mTOR signaling, thereby promoting mitochondrial turnover. These effects were confirmed in cardiomyocytes, where AMPK knockdown abrogated ULK1 activation and mitophagy under conditions of low amino acid availability. Together, these findings uncover a novel mechanism by which DPR attenuates cardiac inflammation and supports mitochondrial homeostasis, highlighting its therapeutic potential for enhancing cardiovascular health during obesity-mediated inflammaging.

Keywords:  bioenergetics; fission; fusion; heart; mitochondria; obesity; quality control

DOI:  https://doi.org/10.1111/acel.70386
ASN Neuro. 2026 ;18(1): 2610198

Loss of Fatty Acid Oxidation by Neural Stem and Progenitor Cells Increases Proliferation but Does Not Improve Long-Term Neurogenesis After Mild Traumatic Brain Injury.

Javier Allende Labastida, Regina F Fernandez, Tiffany Chu, Noelle Puleo, Maria Shishikura, Michael J Wolfgang, Joseph Scafidi, Susanna Scafidi.

  Neurogenesis in the dentate gyrus of the hippocampus is a conserved and highly regulated process throughout the lifespan. Hippocampal neural stem and progenitor cells (NSPCs) can either transition into an activated proliferative state or remain quiescent. Accumulating data suggests that mitochondrial fatty acid β-oxidation is important in maintaining NSPCs quiescence under normal physiological conditions; however, the contribution of this pathway in NSPCs following brain injury remains unknown. While severe traumatic brain injury (TBI) is characterized by increased NSPCs proliferation in the hippocampus, the extent of this proliferative response after mild TBI, the most prevalent form of TBI, has not been fully delineated. Using closed head injury as a model of mild TBI and a brain-specific knockout mouse of carnitine palmitoyltransferase 2 (CPT2; an obligate gene in mitochondrial fatty acid β-oxidation), we investigated the role of fatty acid oxidation in hippocampal NSPCs proliferation in naïve and injured male and female mice. Our results show that loss of CPT2 in the brain does not affect hippocampal proliferation in naïve mice. Furthermore, mild TBI upregulates proliferation at day 3 post-injury, and is further increased only in male CPT2-deficient mice. Despite the post-injury increase in hippocampal NSPCs proliferation in CPT2B-/- mice, long-term neurogenesis remained unchanged. Together, these data provides a new insight into the metabolic regulation of NSPCs neurogenesis in the hippocampus following mild traumatic brain injury.

Keywords:  Fatty acid oxidation; hippocampus; mild traumatic brain injury; neural stem and progenitor cells; proliferation

DOI:  https://doi.org/10.1080/17590914.2025.2610198
Aging Cell. 2026 Feb;25(2): e70378

Deficiency of Microglial-Derived Spp1 Exacerbates Age-Related Memory Decline by Impairing Mitochondrial Complex I Function.

Meiling Wang, Yumin Chang, Aojie He, Jing Yang, Ang Li, Hongqin Wang, Kah-Leong Lim, Xing Guo, Chengwu Zhang, Li Lu.

  Age-related memory decline is a hallmark of brain aging and a primary risk factor for neurodegenerative disorders. Microglia play a crucial role in preserving memory function by maintaining brain homeostasis through phagocytosis, yet the specific mechanisms governing this protective function remain elusive. In the present study, we identified a population of Secreted Phosphoprotein 1 (Spp1)-positive microglia in both aged mouse and human brains. To investigate the role of microglial Spp1 in aging, we generated microglia-specific Spp1 knockout (Spp1-cKO) mice. We demonstrate that Spp1 deficiency selectively precipitates memory deficits in aged mice, without affecting memory function in young mice, indicating an age-dependent reliance on Spp1 signaling. Microglial phagocytic capacity positively correlates with Spp1 levels and is diminished by Spp1 deficiency. Mechanistically, Spp1 deficiency leads to the downregulation of the AKT/mitochondrial complex I pathway, thereby compromising microglial oxidative phosphorylation and function. Notably, microglia-specific overexpression of Spp1 partially ameliorates the age-related phenotypes induced by Spp1 deficiency. In conclusion, this study is the first to reveal the crucial role of microglial Spp1 in brain aging and to uncover its underlying mechanism, providing novel insights into age-related memory decline.

Keywords:  ATP; Spp1; age‐related memory decline; microglia; mitochondrial complex I

DOI:  https://doi.org/10.1111/acel.70378
Sci Rep. 2026 Jan 17.

Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice.

Olivier Reynaud, Marie-Belle Ayoub, Jean-Philippe Leduc-Gaudet, Marina Cefis, Marc P Lussier, Sabah Na Hussain, Gilles Gouspillou.

Duchenne Muscular Dystrophy (DMD) is the most common childhood muscular disorder. Mitochondrial dysfunctions are key disease features of the disease, and strategies that improve mitochondrial health have emerged as promising to slow disease progression. Emerging evidence indicates that impaired/insufficient mitophagy may contribute to the accumulation of mitochondrial dysfunction seen in patients and animal models of DMD. We therefore hypothesized that overexpressing Parkin, a key mitophagy regulator, may improve mitochondrial and muscle health in a mouse model of DMD. To this end, Parkin was overexpressed using intramuscular injections of adeno-associated viruses performed in 5-week-old and 18-week-old D2.B10-Dmdmdx/J mice (D2.mdx), a widely used mouse model of DMD. Four and 16 weeks of Parkin overexpression initiated in 5-week-old and 18-week-old D2.mdx, respectively, resulted in muscle hypertrophy, as indicated by an increase in muscle mass and fiber cross-sectional area. While Parkin overexpression did not impact maximal mitochondrial respiration or mitochondrial content, it increased the Acceptor Control Ratio, an index of mitochondrial bioenergetic efficiency. Parkin overexpression also decreased mitochondrial H2O2 emission, a surrogate for mitochondrial ROS production. However, Parkin overexpression failed to reduce the proportion of fibers with central nuclei and markers of muscle damage and/or necrosis. Taken all together, our results indicate that Parkin overexpression can attenuate muscle atrophy, improve mitochondrial bioenergetics and lower mitochondrial ROS production in a mouse model of DMD. These findings showcase the partial beneficial effects of overexpressing Parkin in ameliorating some, but not all, pathological features observed in a mouse model of DMD.

DOI: https://doi.org/10.1038/s41598-025-34223-9
Am J Physiol Heart Circ Physiol. 2026 Jan 22.

Mitochondrial DNA is an important signaling molecule in cardiovascular aging and pathophysiology.

Yutao Hua, Yuxin Chu, Sarah Fu, Armaan Verma, Jianhua Zhang, Palaniappan Sethu, Timmy Lee, Min Xie.

  Mitochondrial DNA (mtDNA) has emerged as a key signaling molecule, extending beyond its primary role in supporting energy production. Its replication, release, and degradation are tightly regulated, and their dysregulation can activate immune pathways, including TLR9, cGAS-STING, and inflammasomes. In this review, we summarize recent advances in understanding mtDNA biology, including mechanisms of replication and release, recognition by pattern recognition receptors, and its impact on disease. We highlight evidence linking mtDNA to cardiovascular disease, as well as the aging-related chronic kidney disease, lung disorders, and neurodegeneration, and discuss the utility of circulating mtDNA copy number as a biomarker. Finally, we outline therapeutic strategies to reduce mtDNA release, block its sensing, and enhance clearance via autophagy/mitophagy. These findings underscore mtDNA as both a driver of pathology and a promising target for diagnosis and therapy across multiple organ systems.

Keywords:  aging; cardiovacular diseases; inflammation; mitochondrial DNA

DOI:  https://doi.org/10.1152/ajpheart.00686.2025
Adv Sci (Weinh). 2026 Jan 21. e18084

Single-Cell Mitochondrial Lineage Tracing Decodes Fate Decision and Spatial Clonal Architecture in Human Hematopoietic Organoids.

Yan Xue, Junhao Su, Yiming Chao, Lu Liu, Xinyi Lin, Yang Xiang, Mun Kay Ho, Zezhuo Su, Junyi Chen, Zhuojuan Luo, Chengqi Lin, Ruibang Luo, Theo Aurich, Jianfeng Wu, Kelvin Sin Chi Cheung, Yuanhua Huang, Joshua W K Ho, Ryohichi Sugimura.

  Lineage tracing at single-cell resolution is vital for mapping cell fate decisions, yet synthetic barcoding faces limitations in precision, diversity, and toxicity-especially in human pluripotent stem cells (hPSCs). Here, we repurpose naturally occurring somatic mutations in mitochondrial transcripts from single-cell RNA sequencing as endogenous genetic barcodes. By enriching mitochondrial reads and applying a robust computational pipeline, we identified clonally informative variants to trace hematopoietic lineage emergence from hPSCs during early embryogenesis. Integrating mitochondrial barcoding with synthetic lineage tracing, we modeled embryonic tissue development and reconstructed the transcriptional logic and regulatory networks driving fate specification using a dynamical systems model. Extending this approach to spatial transcriptomics, we mapped the clonal architecture of human embryonic organoids, revealing spatial zonation orchestrated by NOTCH-mediated crosstalk between stromal cells and hematopoietic progenitors. This multimodal strategy links clonal dynamics with niche-driven fate decisions, offering a scalable, non-invasive method to dissect tissue organization in development and disease. Together, our work establishes a scalable, non-invasive multimodal framework that leverages endogenous mitochondrial DNA variants to reconstruct high-resolution spatiotemporal clonal dynamics and decode niche-driven fate decisions in a human stem cell-derived model. This approach provides a powerful strategy for dissecting tissue self-organization in development and disease.

Keywords:  cell fate decisions; hematopoietic organoids; mitochondrial DNA variant; single‐cell lineage tracing; spatial transcriptomics

DOI:  https://doi.org/10.1002/advs.202518084
Reproduction. 2026 Jan 23. pii: xaag006. [Epub ahead of print]

CRISPR/Cas9-mediated SLC2A1 gene knockout changes in energy metabolism and cellular behavior in human trophoblasts.

Hahyun Park, Seung-Min Bae, Taeyeon Hong, Gwonhwa Song, Whasun Lim.

  Glucose transport across the placenta is essential for fetal growth and development. Glucose transporter 1 (GLUT1), encoded by the SLC2A1 gene, plays a central role in mediating maternal-fetal glucose exchange. Dysregulation of placental glucose transport is implicated in pregnancy-related complications, such as preeclampsia and fetal growth restriction (FGR); however, the mechanistic role of SLC2A1 in trophoblast function remains poorly defined. To functionally validate the role of SLC2A1 in human trophoblasts, we used CRISPR/Cas9-mediated knockout of the SLC2A1 gene, enabling complete and permanent loss of SLC2A1 expression. In the resulting SLC2A1 knockout (KO) human trophoblast HTR8/SVneo cells, SLC2A1 depletion induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS), leading to increased mitochondrial respiration, ATP production, mitochondrial calcium overload, and elevated mitochondrial ROS generation. These changes were accompanied by enhanced endoplasmic reticulum (ER) stress, as shown by the upregulation of p-PERK, IRE1α, and GRP78, as well as increased autophagic activity indicated by LC3B-II and p62 accumulation. Notably, mTOR signaling was also upregulated, suggesting a feedback loop that regulates autophagy. The loss of SLC2A1 impaired the PI3K/AKT pathway, reduced trophoblast migration and 3D spheroid formation, and disrupted epithelial-mesenchymal transition (EMT)-like properties. These findings demonstrate that SLC2A1 is essential for maintaining trophoblast energy homeostasis, redox balance, and invasive capacity; its deficiency triggers mitochondrial and ER stress responses that may contribute to placental dysfunction during early pregnancy.

Keywords:  CRISPR/Cas9; SLC2A1; Trophoblasts; autophagy; metabolic reprogramming

DOI:  https://doi.org/10.1093/reprod/xaag006
Sci Rep. 2026 Jan 21.

ATF4 regulates mitochondrial dysfunction and mitophagy, contributing to corneal endothelial apoptosis.

Saba Qureshi, Stefan Y Kim, Stephanie Lee, Lukas Ritzer, William Steidl, Gayle Joliet Krest, Anisha Kasi, Varun Kumar.



Keywords:  ATF4; Cell survival; ER stress; Mitochondrial stress; Mitophagy

DOI:  https://doi.org/10.1038/s41598-026-36453-x
Case Rep Ophthalmol. 2026 Jan-Dec;17(1):17(1): 75-80

Leber Hereditary Optic Neuropathy-Associated Novel Mutation in MT-RNR2 Gene: A Case Report.

Sara KamaliZonouzi, Jonathan Micieli.

   Introduction: Leber hereditary optic neuropathy (LHON) is a hereditary optic neuropathy mainly caused by mutations at 1,178, 14,484, and 3,460 in mitochondrial DNA. Patients with LHON have a higher risk of developing multiple sclerosis (MS), a coexistence also known as Harding's syndrome. A growing body of evidence shows that other mitochondrial and non-mitochondrial mutations can lead to LHON and Harding's syndrome. Herein, we report a novel mutation in MT-RNR2 resulting in LHON.
Case Presentation: A 35-year-old woman with bilateral painless optic neuropathy presented to neuro-ophthalmology clinic. Her blood work-up did not reveal any nutritional deficiencies, and she did not respond to steroid therapy. Genetic test revealed a m.1737A>G mutation in MT-RNR2 gene with 99.9% penetrance; therefore, she was diagnosed with LHON.
Conclusion: MT-RNR2 gene mutation was the possible cause for LHON in this patient. Herein, we describe a novel mutation and associated clinical features. This case report also underscores the importance of considering LHON as a differential diagnosis for optic neuritis, even in a patient with an established MS.

Keywords:  Case report; Hereditary optic neuropathy; Leber hereditary optic neuropathy; RNR2; m.1737A>G

DOI:  https://doi.org/10.1159/000550116
Brain. 2026 Jan 22. pii: awag023. [Epub ahead of print]

Successful treatment of neonatal COQ2 deficiency with 4-hydroxybenzoic acid.

Juliane Münch, Thomas Strahleck, Annette Seibt, Sander H J Smits, Sonja Herbrich, Ann-Katrin Hohnecker, Bernhard Wilhelm, Neysan Rafat, Christof Reihle, Christian Stirnkorb, Nadiya Parczyk, Nastassja Himmelreich, April Dinwiddie, Ertan Mayatepek, Diran Herebian, Luis C López, Felix Distelmaier.

DOI: https://doi.org/10.1093/brain/awag023
Front Immunol. 2025 ;16 1670379

Bioactives and exercise synergize to modulate AMPK and inflammation.

ZhaoHui Sheng, Quan Luo, XianChu Liu, Xingjie Yang.

  AMP-activated protein kinase (AMPK) regulates energy homeostasis and immune responses, making it a key target for immunometabolic disorders like obesity, insulin resistance, and neurodegenerative diseases. This review explores the synergistic effects of plant-derived bioactives (e.g., quercetin, resveratrol, curcumin) and exercise on AMPK signaling, focusing on metabolic and immunological outcomes. A systematic search (PubMed, Scopus, Web of Science, up to June 2025) identified 14 preclinical studies showing that combined interventions enhance AMPK phosphorylation, mitochondrial biogenesis, glucose uptake, and lipid oxidation while reducing pro-inflammatory cytokines (e.g., TNF-α, IL-6) and NF-κB signaling via SIRT1/PGC-1α/Nrf2 pathways. Tissue-specific effects in skeletal muscle, heart, brain, liver, and adipose tissue highlight their therapeutic potential. Variability in study designs and limited clinical data necessitate further mechanistic studies, particularly on epigenetic regulation (e.g., histone acetylation, miRNAs), to optimize personalized non-pharmacological strategies.

Keywords:  AMPK signaling; immunometabolism; inflammation; mitochondrial biogenesis; natural bioactives; physical activity

DOI:  https://doi.org/10.3389/fimmu.2025.1670379
EMBO Rep. 2026 Jan 20.

Hyperactivation of mTORC1 blocks stem cell fate transitions through TFE3-NuRD association.

Peizhi Li, Shuhui Xu, Xinyu Wu, Yin Gao, Tanveer Ahmed, Yinghua Huang, Dajiang Qin, Baoming Qin, Lulu Wang, Xueting Xu.

  Mechanistic target of rapamycin complex 1 (mTORC1) integrates signals from nutrients, growth factors, and cellular stress to regulate biosynthesis and maintain homeostasis. Dysregulated mTORC1 disrupts stem cell homeostasis and impairs cell fate transitions in vivo and in vitro. Previous studies have shown that mTORC1 hyperactivation promotes nuclear translocation of TFE3, blocking pluripotency exit in both mouse and human naïve embryonic stem cells. Similarly, our earlier work has demonstrated that sustained mTORC1 activation impedes somatic cell reprogramming via the transcriptional coactivator PGC1α. This raises the question of how mTORC1 coordinates gene transcription across distinct transitions in pluripotent cells. Here, we show that TFE3 mediates the transcriptional blockade induced by mTORC1 hyperactivation during reprogramming. Notably, during both pluripotency exit and reprogramming, TFE3 recruits the NuRD corepressor complex to repress genes essential for cell fate transitions. These findings uncover a shared mechanism by which mTORC1 and TFE3 regulate stem cell identity, highlighting the dual regulatory role of TFE3 and its potential implications in development, aging, and tumorigenesis.

Keywords:  NuRD Complex; Pluripotency Exit; Somatic Cell Reprogramming; TFE3; mTORC1

DOI:  https://doi.org/10.1038/s44319-025-00544-z