bims-polgdi 2026-04-19 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2026–04–19
forty papers selected by
Luca Bolliger, lxBio

Adenine Nucleotide Translocase: From Nucleotide Carrier to a Modulator of Mitochondrial Bioenergetics, Quality Control, and Cellular Communication.
Mitochondrial transfer as a driver of immune microenvironment remodeling.
Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology.
The Caenorhabditis elegans Mitochondrial Electron Transport Chain: its role in Adaptation, Longevity, and Biotechnology.
Diagnostic Criteria and Management of MELAS and Stroke-Like Episodes: Consensus-Based Statements.
Blood mtDNA markers of mitochondrial subtype and early-onset Parkinson's disease biology.
Rare genetic diseases associated with G-quadruplex-induced replication stress.
Therapeutic mitochondria transplants made more efficient with targeting tool.
Mitochondrial Fission and Fusion Disorders and Autophagy Abnormalities in Parkinson's Disease.
Irisin as a Regulator of Brain Energy Homeostasis: Implications for Age-Related Neurodegenerative Diseases.
Mitochondrial DNA (MtDNA) 3243 A>G mutation associated with recurrent cholangitis post-Kasai procedure in biliary atresia.
Comparative analysis of muscle pathologies and metabolic signaling in mouse models of mitochondrial dysfunction.
Beyond the genome: clinical challenges in diagnosing LONP1-related mitochondrial disorders.
The role of exercise-mediated mitochondrial quality control remodeling in aging.
Medics for Rare Disease: advocating for rare disease training.
Mitochondrial Transplantation in the Eye: A Review and Evaluation of Surgical Approaches.
Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.
Extension of Lifespan and Amelioration of Alzheimer's Disease Phenotypes by Genetic Manipulation of Mitochondrial NAD+/NADH Ratio.
Beyond the neuron: Exosomes as intercellular modulators of mitochondrial networks in the pathogenesis and treatment of Alzheimer's disease.
Bayesian quantitative decision-making framework in cell and gene therapy development for rare diseases.
5' UTR length shapes alternative N-terminal protein isoforms across cancers and in rare disease.
Schisandrin B confers multi-organ protection via regulation of mitochondrial homeostasis: mechanistic integration, organ-specific differences, and translational challenges-a review.
Cell-type-targeted mitochondrial transplantation rescues cell degeneration.
Exploring Stem Cell Based Senotherapeutic Strategies for Targeting Cellular Senescence in Brain Aging.
Molecular mechanisms of PINK1/Parkin-mediated mitochondrial quality control.
Therapeutic and mechanistic insights on mitochondrial transplantation in kidney disease.
Cesarean delivery in a pregnant woman with Ellis-van Creveld syndrome: a case report.
Mitochondrial Enzymes Mimetic Ultrasmall Palladium Nanozymes Prevent Senescence and Neurodegeneration Through Metabolic Reprogramming.
Ancient Mitochondrial Genetic Variant, Modern-day Pandora's Box.
The Roles of Macrophage Lineage Cells (MLCs) in Brain Aging.
Sulfide:quinone oxidoreductase drives mitochondrial supersulfide metabolism to regulate bioenergetics and longevity in eukaryotes.
Tau-induced mitochondrial reverse electron transport drives neurodegeneration.
Current challenges in the development of liposomes to target mitochondria.
Mini-Galaxy: Rethinking Complex Human Diseases Through the Lens of Systems Biology and Multilayered AI Network Perspectives.
MitoChontrol: Adaptive mitochondrial filtering for robust single-cell RNA sequencing quality control.
Orphan Drug Approval in Canada, 1999-2022: A Cross-sectional Study.
Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.
Stem cells enhance mitochondrial function in experimental Huntington's disease.
Association of Mitochondrial DNA Levels in Peripheral Blood Leukocytes With Physical Performance in Older Adults.
Learning to take it personally: Precision drug repurposing through patient-specific loss on knowledge graphs using Biobank data.

Cells. 2026 Apr 02. pii: 646. [Epub ahead of print]15(7):

Adenine Nucleotide Translocase: From Nucleotide Carrier to a Modulator of Mitochondrial Bioenergetics, Quality Control, and Cellular Communication.

Ursula Rauch-Kroehnert, Jacqueline Heger, Ulf Landmesser, Andrea Dörner.

  Adenine nucleotide translocase (ANT) has traditionally been defined as the ADP/ATP exchanger of the inner mitochondrial membrane. However, accumulating mechanistic evidence reveals a substantially broader functional spectrum that extends beyond nucleotide transport. In this review, we integrate these advances into a unified conceptual framework that positions ANT isoforms as modulators of mitochondrial bioenergetics, quality control, and cellular communication. Beyond its canonical exchange activity, ANT influences permeability transition thresholds and membrane potential stability, participates in regulated uncoupling and redox control, and contributes to inner membrane organization and cristae integrity. ANT further modulates TIMM23-dependent protein import and PINK1-Parkin-mediated mitophagy, thereby shaping mitochondrial quality control decisions. In addition, ANT regulates mitochondrial nucleic acid release and inflammasome activation, linking bioenergetic imbalance to innate immune signaling. Emerging evidence for alternative subcellular localizations suggests that ANT-dependent signaling extends mitochondrial state information to extracellular and intercellular contexts. Collectively, these findings support an expanded view of ANT as a multifunctional modulator linking mitochondrial energetic state to stress adaptation, inflammatory signaling, and tissue-level communication.

Keywords:  adenine nucleotide translocase; dsRNA transport; extracellular vesicles; immunometabolism; mitochondrial dynamics; mitochondrial permeability transition pore; mitochondrial signaling; mitochondrial uncoupling; mitophagy; mtDNA stability

DOI:  https://doi.org/10.3390/cells15070646
Front Immunol. 2026 ;17 1743261

Mitochondrial transfer as a driver of immune microenvironment remodeling.

Xiaoya Zhang, Danmei Zhang, Jin Guo, Chunxia Shi, Zuojiong Gong.

  Mitochondria are central regulators of immunometabolism, and emerging evidence identifies intercellular mitochondrial transfer as a key driver of immune microenvironment remodeling. Beyond energy production, transferred mitochondria reshape immune niches by reprogramming metabolic fitness, redox balance, inflammatory tone, and immune cell interactions. Through multiple transfer routes, including tunneling nanotubes, extracellular vesicles, and gap junctions, mitochondrial exchange modulates immune activation, immunosuppression, and tolerance across diverse physiological and pathological contexts. In this review, we summarize current mechanisms of mitochondrial transfer and highlight how this process directionally remodels the immune microenvironment in inflammation, cancer, and autoimmune diseases. We further discuss therapeutic strategies aimed at modulating mitochondrial transfer to reprogram immune responses, providing new perspectives for immunomodulation and disease intervention.

Keywords:  cancer; immune cell; immune microenvironment; inflammation; mitochondria transfer

DOI:  https://doi.org/10.3389/fimmu.2026.1743261
HGG Adv. 2026 Apr 10. pii: S2666-2477(26)00054-0. [Epub ahead of print] 100614

Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology.

Nikki D Russell, Jonathan M Downie, Mark B Bromberg, Stefan M Pulst, Lynn B Jorde.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with multiple genetic causes. Given the strong evidence of mitochondrial dysfunction in ALS, this study aimed to identify genetic contributors to ALS by focusing on genes involved in mitochondrial function. Whole-genome and exome sequencing data from 1,034 ALS cases were analyzed using two distinct computational tools, which ranked candidate genes based on functional relevance to ALS. POLG, the sole mitochondrial DNA polymerase, emerged as a top candidate gene. RNA-seq analysis revealed that among genes upregulated in samples with a POLG variant, there was an enrichment for mitochondrial pathways such as translation, localization, and mitophagy. It also revealed variants in POLG and SOD1, a well-known ALS gene, to be the most enriched in samples with expression profiles of mitochondrial-related genes that differed most from those of unaffected controls. POLG variant carriers also exhibited an increased burden of mitochondrial genome variants, a pattern shared by carriers of variants in other genes involved in mitochondrial DNA maintenance. Additionally, POLG variant carriers had elevated mitochondrial DNA copy number (mtDNA-CN), similar to carriers of variants in mitophagy-related genes, suggesting impaired mitophagy. Together, these findings implicate POLG as an ALS-associated gene and link mitochondrial DNA maintenance defects, altered expression of mitochondrial-related pathways, and impaired mitophagy to ALS etiology.

DOI: https://doi.org/10.1016/j.xhgg.2026.100614
Exp Cell Res. 2026 Apr 13. pii: S0014-4827(26)00143-6. [Epub ahead of print] 115026

The Caenorhabditis elegans Mitochondrial Electron Transport Chain: its role in Adaptation, Longevity, and Biotechnology.

Estefani Yaquelin Hernández-Cruz, Salvador Uribe-Carvajal.

  In Caenorhabditis elegans (C. elegans) the mitochondrial electron transport chain (ETC) exhibits remarkable functional plasticity. This review summarizes the composition, regulation, and adaptive roles of complexes I-V. Depending on oxygen availability, the ETC uses either ubiquinone (UQ) or rhodoquinone (RQ), an ancestral strategy for hypoxia or high hydrogen sulfide (H2S) conditions. Mild ETC impairments can extend lifespan through redox signaling, mitohormesis, and activation of the mitochondrial unfolded protein response. These processes likely represent conserved mechanisms of bioenergetic adaptation and longevity. Moreover, C. elegans server as a translational model for human mitochondrial diseases and for screening mitochondrial or antiparasitic compounds.

Keywords:  Caenorhabditis elegans; electron transport chain; longevity; mitochondria; rhodoquinone

DOI:  https://doi.org/10.1016/j.yexcr.2026.115026
Eur J Neurol. 2026 Apr;33(4): e70588

Diagnostic Criteria and Management of MELAS and Stroke-Like Episodes: Consensus-Based Statements.

Michelangelo Mancuso, Marcello Bellusci, Valerio Carelli, Irenaeus de Coo, Daria Diodato, Felix Distelmaier, Omar Hikmat, Michio Hirano, Rita Horvath, Amel Karaa, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Chiara La Morgia, Piervito Lopriore, Mika Henrik Martikainen, Robert McFarland, Olimpia Musumeci, Robert D S Pitceathly, Guido Primiano, Shamima Rahman, Fernando Scaglia, Andrew Schaefer, Manuel Schiff, Luisa Semmler, Costanza Lamperti, Serenella Servidei.

   BACKGROUND AND PURPOSE: Mitochondrial Encephalomyopathy, Lactic acidosis and Stroke-like episodes (MELAS) is a rare multisystem mitochondrial disorder with clinical heterogeneity. Diagnostic criteria and management strategies for MELAS and mitochondrial stroke-like episodes (SLE) remain inconsistent. This work provides international consensus recommendations on the definition, diagnosis, and management of MELAS and SLE in pediatric and adult populations.
METHODS: An international Delphi consensus process was conducted within the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD), in collaboration with the US Mitochondrial Medicine Society, the ERN for Hereditary Metabolic Disorders (MetabERN), and patient representatives. Following a systematic literature review, 54 statements addressing diagnostic definitions and management of MELAS were evaluated. Statements not reaching consensus were revised and re-evaluated during a face-to-face meeting.
RESULTS: Consensus supported defining MELAS as a clinical syndrome characterized by one or more SLE in the context of mitochondrial dysfunction caused by a pathogenic mitochondrial DNA variant, particularly m.3243A>G in MT-TL1. The use of terms such as "MELAS-like" or "MELAS spectrum" was discouraged. The panel agreed that the efficacy of L-arginine, L-taurine, L-citrulline, coenzyme Q10, vitamins, and other supplements remains unproven and requires validation in clinical trials. Antiseizure medications should be initiated promptly when seizures are suspected during SLE, and intravenous corticosteroids may be beneficial acutely. Multidisciplinary management of neurological, neuropsychiatric, and systemic complications was endorsed.
CONCLUSIONS: This international consensus provides updated definitions and practical guidance for the diagnosis and management of MELAS and SLE, aiming to harmonize clinical practice and inform future evidence-based research.

Keywords:  MELAS; consensus; diagnostic criteria; management; primary mitochondrial diseases; recommendations

DOI:  https://doi.org/10.1111/ene.70588
Brain. 2026 Apr 16. pii: awag135. [Epub ahead of print]

Blood mtDNA markers of mitochondrial subtype and early-onset Parkinson's disease biology.

Anne Grünewald, Felix Knab, Milan Zimmermann, Zied Landoulsi, Jenny Ghelfi, Soraya Hezzaz, Sylvie Delcambre, Maria Zarani, Radu-Gabriel Copie, Benjamin Röben, Karan Sharma, Piero Parchi, Anna Katharina von Thaler, Ulrike Sünkel, Claudia Schulte, Ann-Kathrin Hauser, Christine Klein, Thomas Gasser, Bernd Wissinger, Kathrin Brockmann, Patrick May, Gerrit Machetanz, Julia C Fitzgerald.

  Mitochondrial dysfunction is central to the pathogenesis of Parkinson's disease (PD), integrating both genetic and environmental factors. Therefore, reliable blood-based biomarkers reflecting mitochondrial alterations are needed. Emerging evidence suggests that somatic changes to mitochondrial DNA (mtDNA) may reflect early disease-associated processes relevant to PD conversion and clinical manifestation. In this study, we analysed somatic mtDNA major arc deletions as a measure of mitochondrial genome integrity and evaluated 7S DNA abundance as well as copy number as complementary readouts in whole blood (n=776) from a large cohort, including idiopathic and genetic PD patients, individuals at risk, PD converters, patients with primary mitochondrial disease, and healthy controls. This work was complemented by analyses in CSF samples (n=72). Finally, mtDNA measures were integrated with genetic, protein, and clinical data, including mitochondrial polygenic risk scores, alpha-synuclein seeding assays, and serum neurofilament light chain levels. In blood, the strongest effects occurred in PINK1/PRKN-PD (deletions: P<0.0001; 7S DNA: P<0.0001) and early-onset idiopathic PD (7S DNA: P=0.0009-0.0030). Individuals with prodromal signs conferring a high risk for PD also showed increased mtDNA deletions (P=0.0045) and reduced 7S DNA (P=0.0046). In PD converters, these alterations were detectable prior to clinical diagnosis (deletions: P=0.0024; 7S DNA: P=0.0091). In CSF-derived extracellular vesicles, we observed an age-associated increase in mtDNA copy number in healthy controls (R2=0.121, P=0.035) that was absent in idiopathic PD (R2=0.014, P=0.548). Across all PD patients, those with the highest mtDNA deletion burden and lowest 7S DNA exhibited a higher risk of developing cognitive impairment and depression, while also showing a longer time to postural instability (deletions: P=0.0187; 7S DNA: P=0.0281). Integration of mtDNA readouts, mitochondrial polygenic risk scores, alpha-synuclein seeding, and serum neurofilament light chain levels revealed complementary contributions to biological heterogeneity in PD, with receiver operating characteristic analyses showing moderate group-level discrimination using mtDNA measures alone (AUC=0.66) and substantially improved discrimination when combined with alpha-synuclein and neurodegeneration markers (AUC up to 0.96). Alpha-synuclein seeding activity was associated with later age at onset, whereas mtDNA deletion burden showed an inverse association, indicating that these biomarkers capture distinct biological dimensions of PD. MtDNA damage markers, particularly deletion burden, capture mitochondrial dysfunction arising from both genetic and environmental influences and are detectable across early clinical stages of PD. While not serving as stand-alone diagnostic biomarkers, mtDNA measures provide complementary biological information within a multimodal framework and may support patient stratification based on mitochondrial involvement using a minimally invasive approach.

Keywords:  7S DNA; Parkinson’s disease; biomarker; mitochondria; mtDNA copy number; mtDNA deletion; stratification

DOI:  https://doi.org/10.1093/brain/awag135
Commun Biol. 2026 Apr 13. pii: 522. [Epub ahead of print]9(1):

Rare genetic diseases associated with G-quadruplex-induced replication stress.

Lauren M Herr, Swagata Mukhopadhyay, Olivia M Anderson, Tucker H Couch, Cate M Jones, Robert M Brosh, Martina Rossi.

DNA replication stress is incurred by endogenous or environmental challenges to replication fork progression that impede faithful genome duplication. Genomic G-quadruplexes (G4s) are DNA secondary structures that present a substantial barrier for passage of the replisome, and DNA synthesis past these structures requires dynamic remodeling by specialized helicases, translocases, and other G4-binding proteins to facilitate G4 resolution or bypass. Mutations in the genes encoding these auxiliary replication proteins are linked to hereditary disorders presenting with a range of clinical features, including immunodeficiency, growth restriction, congenital abnormalities, and cancer predisposition, demonstrating that these G4-metabolizing proteins also play broader roles in genome biology such as the replication stress response or DNA repair. Here, we review rare diseases linked to mutations in G4-resolving and binding proteins, with an emphasis on molecular defects in G4 metabolism that incur replication stress and genomic instability. We discuss differences in G4 substrate specificity and mechanism of G4-interactive helicases, as revealed by high-resolution structural data. Furthermore, we address outstanding questions that provide insight into the etiology of rare diseases marked by dysregulated G4 homeostasis and may inform diagnosis and potential therapeutic strategies.

DOI: https://doi.org/10.1038/s42003-026-09966-4
Nature. 2026 Apr 15.

Therapeutic mitochondria transplants made more efficient with targeting tool.

Samantha J Krysa, Jonathan R Brestoff.



Keywords:  Biotechnology; Cell biology; Diseases

DOI:  https://doi.org/10.1038/d41586-026-00910-4
Neurochem Res. 2026 Apr 11. pii: 136. [Epub ahead of print]51(2):

Mitochondrial Fission and Fusion Disorders and Autophagy Abnormalities in Parkinson's Disease.

Yufei Liu, Haoran Li, Jie Bai.



Keywords:  Mitochondria; Mitochondrial autophagy; Mitochondrial fission and fusion; Parkinson’s disease

DOI:  https://doi.org/10.1007/s11064-026-04752-4
Cells. 2026 Mar 28. pii: 603. [Epub ahead of print]15(7):

Irisin as a Regulator of Brain Energy Homeostasis: Implications for Age-Related Neurodegenerative Diseases.

Bartosz Osuch, Patrycja Młotkowska, Elżbieta Marciniak, Tomasz Misztal.

  Aging is associated with disturbances in brain energy metabolism, mitochondrial dysfunction, and increased oxidative stress, all of which increase neuronal vulnerability and contribute to the development of neurodegenerative disorders. Growing evidence indicates that physical exercise exerts neuroprotective effects through the release of exerkines-exercise-induced signaling molecules that mediate communication between peripheral tissues and the brain. Among them, irisin, a proteolytic cleavage product of the membrane protein FNDC5, has emerged as an important mediator of the muscle-brain axis. This review summarizes current knowledge on the molecular mechanisms underlying irisin activity in the central nervous system, with particular emphasis on the AMPK-PGC-1α-FNDC5/BDNF signaling axis, rapid receptor-mediated pathways involving the cAMP/PKA/CREB and ERK/CREB cascades, and the regulation of mitochondrial homeostasis, including biogenesis, dynamics, autophagy, and mitophagy. Experimental studies suggest that irisin may improve neuroplasticity, neuronal survival, mitochondrial function, and reduce oxidative stress, thereby alleviating cognitive deficits in models of aging and neurodegeneration. Although the precise receptor mechanisms and intracellular signaling events remain incompletely understood, accumulating evidence identifies irisin as a promising therapeutic target linking metabolic adaptation with neuroprotection. Further investigation of irisin-dependent pathways may facilitate the development of novel strategies aimed at preserving brain function and delaying the progression of age-related neurodegenerative diseases.

Keywords:  AMPK–PGC-1α; BDNF; FNDC5; irisin; mitochondrial homeostasis; mitophagy; neurodegenerative diseases

DOI:  https://doi.org/10.3390/cells15070603
Transl Pediatr. 2026 Mar 23. 15(3): 94

Mitochondrial DNA (MtDNA) 3243 A>G mutation associated with recurrent cholangitis post-Kasai procedure in biliary atresia.

Jie Sun, Yanan Zhang, Dayan Sun, Jinshi Huang.



Keywords:  Kasai procedure; biliary atresia (BA); cholangitis; liver transplantation; m.3243A>G

DOI:  https://doi.org/10.21037/tp-2026-1-0137
Sci Rep. 2026 Apr 16.

Comparative analysis of muscle pathologies and metabolic signaling in mouse models of mitochondrial dysfunction.

Hiroaki Tamashiro, Kaori Ishikawa, Kazuto Nakada.

  Mitochondria are vital organelles that produce ATP through oxidative phosphorylation, sustaining skeletal muscle, a tissue with high energy demand. When mitochondrial function is impaired, intracellular energy and nutrient balance are disrupted, activating metabolic signaling pathways. However, these responses vary across models, and the relationship between muscle pathology and signaling remains unclear. To address this, we compared soleus muscle pathology in Polgmut/mut mice, a premature aging model, and Mito-mice∆, a mitochondrial disease model. Both exhibited abnormal histochemical activity in mitochondrial respiration complex II and IV, yet differed in severity of mitochondrial accumulation and fiber-type-specific vulnerability. To explore the basis of these differences, we examined metabolic signaling pathways. Notably, phosphorylation levels of AMPK, a key sensor activated in response to altered AMP/ATP ratios, were significantly different between the two models. These findings suggest that muscle pathology induced by mitochondrial dysfunction is determined less by the extent of abnormalities in mitochondrial respiration complexes than by the specific metabolic signaling pathways engaged. This highlights the importance of signaling context in shaping disease mechanisms and underscores the need to consider pathway-specific responses when investigating mitochondrial dysfunction in skeletal muscle.

Keywords:  Metaboloc signaling; Mitochondria; Mouse models; Muscle pathology

DOI:  https://doi.org/10.1038/s41598-026-48532-0
Front Cell Dev Biol. 2026 ;14 1779332

Beyond the genome: clinical challenges in diagnosing LONP1-related mitochondrial disorders.

Qianni Jiang, Jing Duan, Chao Liu, Yuanyuan Zhu, Qi Zeng, Yuhui Hu, Zhiqiang Luo, Dezhi Cao, Jianxiang Liao, Li Chen.

   Background: LONP1 encodes an ATP-dependent protease essential for maintaining mitochondrial homeostasis. LONP1 variants have been associated with cerebral-ocular-dental-auricular-skeletal anomalies syndrome, pediatric cataract, congenital diaphragmatic hernia, and neurodevelopmental disorders; moreover, these variants can be inherited in both autosomal recessive and autosomal dominant modes.
Methods: We conducted a retrospective analysis of the clinical data and genetic test results of a Chinese boy diagnosed as having mitochondrial encephalopathy. Subsequently, we evaluated the pathogenicity of candidate variants and conducted a literature review encompassing 47 cases of LONP1 variants.
Result: The proband was a 4.5-year-old boy who had experienced focal epilepsy seizures since birth. He presented with recurrent seizures and did not respond to anti-seizure medications. He showed global developmental delay, microcephaly, pachygyria, and hyperlactatemia. Initial genetic testing through single and trio whole-exome sequencing before 6 months of age yielded no conclusive results. Recurrent seizures and elevated lactic acid levels at 18 months of age prompted reanalysis with trio whole-exome sequencing, leading to the identification of a likely pathogenic variant in LONP1: c.901C>T (p.Arg301Trp). By 10 months of age, the patient had already developed primary adrenal insufficiency and experienced multiple adrenal crises triggered by respiratory infections, necessitating admission to the intensive care unit. The crises were effectively managed with hydrocortisone. However, despite intensive medical interventions, the patient succumbed to a metabolic crisis triggered by a severe respiratory infection at the age of 4.5 years.
Conclusion: In this study, we discuss the clinical manifestations and genetic features of a pediatric patient with mitochondrial encephalopathy resulting from a rare LONP1 variant, emphasizing the diagnostic and therapeutic challenges of mitochondrial disorders. Furthermore, our findings enhance the understanding of LONP1-related diseases and offer additional evidence supporting the autosomal dominant inheritance pattern of LONP1.

Keywords:  CODAS syndrome; LONP1; adrenal crises; autosomal dominant; mitochondrial encephalopathy

DOI:  https://doi.org/10.3389/fcell.2026.1779332
Front Cell Dev Biol. 2026 ;14 1792645

The role of exercise-mediated mitochondrial quality control remodeling in aging.

Tao Cai, Yating Li, Yunsong Zhang, Chunyan Li, Shanhui Li, Qi Zhang.

  Aging is intimately associated with multisystem functional decline and an increased risk of chronic diseases. A pivotal cytological basis underlying this process is the progressive dysregulation of the mitochondrial quality control (MQC) network. Emerging evidence suggests that MQC is not a singular process but rather a multitiered synergistic system encompassing mitochondrial biogenesis, dynamic remodeling, selective autophagy (mitophagy), proteostasis maintenance, and coordinated mitochondrial-organelle communication. This integrated network is critical for preserving cellular energy homeostasis, redox balance, and stress tolerance. During aging, impairments in mitochondrial genomic coordination, network topology, autophagic flux, and protein import and folding collectively contribute to bioenergetic decline, chronic low-grade inflammation, and metabolic imbalance. As a safe and sustainable nonpharmacological intervention, regular exercise systematically remodels MQC structure and function by integrating signaling axes such as AMPK, SIRT1, and p38 MAPK, thereby promoting coordinated mitochondrial renewal and partially reversing aging-associated mitochondrial dysfunction. On the basis of a systematic elucidation of the core mechanisms of MQC and its dysregulation during aging, this review highlights the differential regulatory effects of distinct exercise modalities-specifically endurance training, high-intensity interval training (HIIT), and resistance training-on mitochondrial dynamics, autophagic flux, proteostasis, and mitochondrial turnover. Furthermore, the intrinsic associations among exercise-MQC coupling, inflammatory responses, metabolic imbalances, and emerging peripheral biomarkers are explored. Finally, current research limitations and challenges in clinical translation are analyzed, and future research directions regarding dose-response relationships, multimodal exercise prescriptions, personalized strategies, and systemic integrated regulation are proposed. This review aims to provide a refined theoretical basis for optimizing exercise-based anti-aging interventions.

Keywords:  age; aging; exercise; mitochondrial quality control; physical training

DOI:  https://doi.org/10.3389/fcell.2026.1792645
Nat Rev Cardiol. 2026 Apr 15.

Medics for Rare Disease: advocating for rare disease training.

Emma Huskinson, Helen Maginnis, Lucy McKay.

DOI: https://doi.org/10.1038/s41569-026-01291-x
bioRxiv. 2026 Apr 07. pii: 2026.04.06.716722. [Epub ahead of print]

Mitochondrial Transplantation in the Eye: A Review and Evaluation of Surgical Approaches.

Bertan Cakir, Tsai-Chu Yeh, Cheng-Hui Lin, Man-Ru Wu, Éric Boilard, Martin Pelletier, Aneal M Singh, Yann Breton, Samir Patel, Tom Benson, David Rp Almeida, Sui Wang, Vinit B Mahajan.

Purpose: Mitochondrial dysfunction contributes to major blinding diseases, including age-related macular degeneration and glaucoma. Although mitochondrial transplantation has shown therapeutic potential in multiple organ systems, translation to the eye remains limited, partly due to uncertainty regarding optimal delivery. We summarize the biologic rationale and preclinical evidence supporting ocular mitochondrial transplantation and present feasibility data evaluating clinically relevant delivery routes.
Methods: We conducted a focused narrative review of ocular mitochondrial transplantation. For feasibility experiments, mitochondria with an endogenous fluorescent dye were isolated from liver donor mice. Postnatal day 7 pups received subretinal injections, and adult CD1 mice received intravitreal injections, including optic nerve head directed delivery. Eyes were analyzed using fluorescence microscopy and immunohistochemistry. Mitochondrial uptake was assessed in cultured retinal pigmental epithelial (RPE) cells using co-incubation assays. Suprachoroidal delivery feasibility was evaluated in cadaveric human near-real surgical specimens using a novel dedicated suprachoroidal injector.
Results: The literature on ocular mitochondrial transplantation remains limited and consists primarily of small preclinical studies using intravitreal delivery and imaging-based detection. In our experiments, intravitreal delivery produced donor signals predominantly within inner retinal layers, with enrichment along retinal nerve fiber bundles when directed toward the optic nerve head. Cultured RPE cells demonstrated dose-dependent uptake of exogenous mitochondria. Subretinal delivery localized donors signal to the RPE and adjacent outer retina. Suprachoroidal injections demonstrated procedural feasibility with reliable access to the suprachoroidal space and visible injectate distribution.
Conclusions: Ocular mitochondrial transplantation is in an early stage of investigation. Our feasibility data indicate that established posterior-segment delivery routes expose distinct retinal compartments and that route selection strongly influences anatomic distribution. Further studies are needed to verify intracellular uptake, define dosing and durability, and evaluate safety in disease-relevant models.

DOI: https://doi.org/10.64898/2026.04.06.716722
Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00193-0. [Epub ahead of print]86(8): 1511-1528.e12

Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.

Lvxin Xie, Shuchao Ren, Li Zhang, Ziqing Wang, Tong Wu, Qing Dai, Shikun Xiang, Zhihua Qian, Yufan Xian, Shutong Xu, Xiao-Lin Chen, Chuan He, Yi Liu, Zhipeng Zhou.

  Mitochondria generate ATP through oxidative phosphorylation (OXPHOS), with core structural subunits encoded by mitochondrial DNA (mtDNA) and translated by mitochondrial ribosomes. However, how mitochondrial translation elongation influences OXPHOS biogenesis remains unclear. Here, we show that in Neurospora crassa, the mitochondrial ribosomal RNA (rRNA) methyltransferase 1 (MRM1) promotes OXPHOS biogenesis by repressing translation elongation independently of its catalytic activity. The N-terminal intrinsically disordered region (IDR) of MRM1 binds simultaneously to mitochondrial ribosomes and mRNAs. Disrupting either interaction accelerates elongation and enhances synthesis of mtDNA-encoded OXPHOS subunits but impairs their co-translational folding and membrane insertion. Pharmacological slowing of mitochondrial translation partially alleviates these defects. The MRM1 IDR is conserved in Ascomycete fungi and is essential for plant infection by Magnaporthe oryzae. Together, our findings identify translation elongation control as a mechanism coordinating mitochondrial protein synthesis and folding during OXPHOS biogenesis and MRM1 as a potential target for broad-spectrum antifungal strategies.

Keywords:  Magnaporthe oryzae; Neurospora crassa; mitochondrial rRNA methyltransferase; mitochondrial translation; oxidative phosphorylation; protein folding; translation elongation

DOI:  https://doi.org/10.1016/j.molcel.2026.03.017
Aging Dis. 2026 Apr 13.

Extension of Lifespan and Amelioration of Alzheimer's Disease Phenotypes by Genetic Manipulation of Mitochondrial NAD+/NADH Ratio.

Suman Rimal, Jae-Hyuk Lee, Yanzi He, Bingwei Lu.

Aging remains the most significant risk factor for common neurodegenerative diseases including Alzheimer's disease (AD). According to the geroscience hypothesis, aging is malleable and that by targeting basic aging physiology, we can alleviate many of the age-related chronic diseases. The common mechanisms driving aging and age-related diseases remain poorly defined. Mitochondrial dysfunction is recognized as a fundamental hallmark of aging, and recent studies implicate mitochondrial reverse electron transport (RET) as a driver of aging. The key outcomes of RET, increased ROS and decreased NAD+/NADH ratio, have both been associated with aging and age-related disease, but the causal relationship remains uncertain. Here we applied causal metabolism to test the role of mitochondrial NAD+/NADH in aging and AD, using Drosophila as a model system. By using a mitochondrial targeted version of Lactobacillus brevis NADH oxidase (LbNox) to boost mitochondrial NAD+/NADH ratio independent of the energy state of the cell, we found that increasing mitochondrial NAD+/NADH ratio in neuronal or muscle tissues is sufficient to extend lifespan. Moreover, boosting mitochondrial NAD+/NADH ratio is beneficial in two independent models of AD, rescuing the proteostasis failure, locomotor and cognitive deficits, and lifespan shortening in these models. Our results identify altered mitochondrial NAD+/NADH ratio as a major contributor to the biological effects of RET on aging and age-related diseases and a potential therapeutic target.

DOI: https://doi.org/10.14336/AD.2026.0011
Alzheimers Dement. 2026 Apr;22(4): e71330

Beyond the neuron: Exosomes as intercellular modulators of mitochondrial networks in the pathogenesis and treatment of Alzheimer's disease.

Liping Xing, Annan Liu, Wei Gao, Jianhui Li, Mingyuan Yao, Jing Song, Peihan Duan, Honglin Li.

  Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by β-amyloid deposition, hyperphosphorylated tau protein, and progressive neuronal loss. Mitochondria form a dynamic interconnected network within the central nervous system, and their dysfunction plays a central role in AD, involving oxidative stress, kinetic dysregulation, and impaired mitochondrial autophagy. As key mediators of intercellular communication, exosomes carry bioactive components that regulate mitochondrial function in recipient cells. This review summarizes advances in research on exosomes as coordinators of the mitochondrial network in the central nervous system, regulating mitochondrial quality control across different neuronal cell types. It systematically outlines the molecular mechanisms by which exosomes modulate mitochondrial function in AD through regulating mitochondrial biogenesis, fusion-fission dynamics, mitochondrial autophagy, and related signaling pathways. Furthermore, it explores the potential of engineered exosome-based targeted therapies for AD intervention, aiming to provide a theoretical foundation and research direction for developing novel therapeutic strategies targeting mitochondrial dysfunction.

Keywords:  Alzheimer's disease; exosomes; mitochondria; neuroprotection; targeted therapy

DOI:  https://doi.org/10.1002/alz.71330
J Biopharm Stat. 2026 Apr 14. 1-24

Bayesian quantitative decision-making framework in cell and gene therapy development for rare diseases.

Rui Kang, Yusuke Yamaguchi, Cong Han.

  Developing drugs including cell and gene therapies for rare diseases presents unique challenges, primarily due to small patient populations and limited clinical data. In such settings, traditional quantitative decision-making (QDM) frameworks, which play a crucial role in guiding go/no-go decisions in proof-of-concept (PoC) studies, often lead to inconclusive decisions due to limited information. This paper is the first study presenting a Bayesian QDM framework specifically tailored to cell and gene therapy candidates in the rare disease space, with an emphasis on borrowing information from external data sources to improve the robustness of QDM. While technical components of Bayesian QDM framework have been established in the literature, our contribution lies in (1) a unified framework accommodating both controlled and uncontrolled PoC studies with hypothetical controls, (2) the systematic integration of power priors with flexible control of information borrowing, and (3) practical implementation guidance through an open-source R Shiny application. The proposed framework offers potential advantages, such as more informed decision-making based on reduced trial durations and improved resource allocation, which are critical for accelerating drug development in rare diseases. Simulation studies and a case study are conducted to illustrate the practical application of Bayesian QDM, demonstrating its benefits in early-stage clinical trials.

Keywords:  Bayesian statistics; Quantitative decision-making; cell and gene therapy; proof-of-concept study

DOI:  https://doi.org/10.1080/10543406.2026.2655410
EMBO Rep. 2026 Apr 13.

5' UTR length shapes alternative N-terminal protein isoforms across cancers and in rare disease.

Jimmy Ly, Eric M Smith, Matteo Di Bernardo, Yi Fei Tao, Elizabeth M Black, Ekaterina Khalizeva, Iain M Cheeseman.

The 5' untranslated region (5' UTR) of an mRNA is classically viewed as a regulatory region that controls the amount of protein production, but not the resulting protein sequence. Here, we demonstrate that 5' UTR length plays a direct role in alternative N-terminal protein isoform production by controlling start codon selection. We find that very short 5' UTRs enhance leaky ribosome scanning, thereby promoting the production of truncated alternative N-terminal protein isoforms. We also show that endogenous changes in 5' UTR length due to alternative transcription initiation can tune the relative abundance of alternative N-terminal isoforms from the same gene. In addition, we identify mutations in rare genetic diseases that alter 5' UTR length, including a deletion in the VHL 5' UTR in von Hippel-Lindau disease that shifts translation toward the shorter VHLp19 isoform. Together, our results implicate 5' UTR length as a determinant of alternative N-terminal isoform production and reveal an underappreciated mechanism by which noncoding changes can reshape the proteome.

DOI: https://doi.org/10.1038/s44319-026-00776-7
Front Pharmacol. 2026 ;17 1781376

Schisandrin B confers multi-organ protection via regulation of mitochondrial homeostasis: mechanistic integration, organ-specific differences, and translational challenges-a review.

Siyi Guo, Fei Yu, Chao Wang, Wenbing Zhao, Xuan Li, Jiayi Liu, Zhida Lyu.

  Schisandrin B (Sch B) is a dibenzocyclooctadiene lignan derived from plants of the Schisandra genus. Owing to its pronounced lipophilicity, Sch B may readily cross biological membranes and is increasingly discussed in association with the regulation of mitochondrial homeostasis. Mitochondrial dysfunction underlies key pathological processes involved in multi-organ injury and a broad range of chronic diseases, manifested as redox imbalance, reduced mitochondrial membrane potential (ΔΨm), impaired ATP production, mitochondrial DNA (mtDNA) damage, disrupted mitochondrial dynamics, failure of mitochondrial quality control, and amplified inflammation, thereby promoting cell death and tissue remodeling. Accumulating evidence in recent years suggests that Sch B exerts biological effects associated with improved mitochondrial function in multiple models involving the liver, kidney, heart, brain, lung, and tumors. However, previous reviews have primarily focused on overall pharmacological activities or individual diseases, and a cross-organ integrative framework with "mitochondria" as the central axis remains limited. Based on current evidence, the mitochondria-related actions of Sch B can be summarized at several complementary levels: maintaining redox balance; stabilizing ΔΨm and potentially modulating the threshold of the mitochondrial permeability transition pore (mPTP); improving calcium homeostasis and bioenergetic output; reshaping the balance between fusion and fission; context-dependently regulating autophagy/mitophagy and autophagic flux; and bidirectionally influencing mitochondria-mediated apoptotic pathways in distinct cellular settings. At the organ level, the effects of Sch B exhibit a "pathology-driven matching" pattern: in acute stresses such as ischemia-reperfusion, Sch B tends to enhance mitochondrial stress tolerance and promote energy recovery; in toxin/drug-induced injury, it more prominently delays membrane structural disruption and oxidative damage; whereas in metabolic chronic diseases, its actions are associated with metabolic flexibility and the continuity of quality control processes. Despite the cross-organ consistency of Sch B in mitochondrial regulation, its translation remains constrained by factors including in vivo exposure, effective intramitochondrial concentration, delivery and targeting strategies, safety boundaries, and interindividual variability. Therefore, this review proposes a multi-organ mechanistic model centered on "mitochondrial homeostasis regulation," providing a theoretical basis for understanding the cross-system effects of Sch B and for future drug development and optimization.

Keywords:  mechanism; mitochondrial homeostasis; multi-organ protection; schisandrin B; translational challenges

DOI:  https://doi.org/10.3389/fphar.2026.1781376
Nature. 2026 Apr 15.

Cell-type-targeted mitochondrial transplantation rescues cell degeneration.

Temurkhan Ayupov, Verónica Moreno-Juan, Serena Curtoni, Alex Fratzl, Upnishad Sharma, Susana Posada-Céspedes, Ramona Ratiu, Rei Morikawa, Alexandra Graff Meyer, Margherita Pezzoli, Glenn Bantug, Morgan Chevalier, Yanyan Hou, Sarah A Nadeau, Álvaro Herrero-Navarro, Vikram Ayinampudi, Elizabeth Kastanaki, Natasha Whitehead, Rebecca A Siwicki, Mariana M Ribeiro, Ji Hoon Han, Annalisa Bucci, Christoph Hess, Simone Picelli, Magdalena Renner, Daniel J Müller, Cameron S Cowan, Simon Hansen, Botond Roska.

A number of currently untreatable diseases, including neurodegenerative disorders, optic nerve atrophy and heart failure, are associated with mitochondrial dysfunction. Transplantation of healthy mitochondria has been proposed as a potential therapeutic strategy1-3. However, the lack of methods to target donor mitochondria to disease-affected cell types limits treatment specificity and efficacy. Here we developed MitoCatch as a system to deliver mitochondria to specific cell types using different types of protein binders. Donor mitochondria are captured by target cells by cell-surface-displayed monospecific binders, mitochondrion-displayed monospecific binders or bispecific binders linking mitochondria to target cells. Using MitoCatch, we show that donor mitochondria are efficiently internalized, exposed to the cytosol, move, and undergo fusion and fission inside target cells. By engineering binders with different affinities, we tune the efficiency of mitochondrial delivery. We demonstrate targeted mitochondrial transplantation to retinal cell types, neurons and cardiac, endothelial and immune cells in humans and mice. Transplanted mitochondria promoted the survival of damaged neurons from an individual with optic nerve atrophy in vitro and after neuronal injury in mice in vivo. MitoCatch is a potential strategy to target disease-affected cell types with mitochondria in organs affected by diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41586-026-10391-0
Stem Cell Rev Rep. 2026 Apr 13.

Exploring Stem Cell Based Senotherapeutic Strategies for Targeting Cellular Senescence in Brain Aging.

Prakshi Sharma, Shalmoli Bhattacharyya.



Keywords:  Aging; Extracellular vesicles; Mitochondria; Neurodegeneration; Secretome; Senescence; Senotherapeutics

DOI:  https://doi.org/10.1007/s12015-026-11117-5
Trends Biochem Sci. 2026 Apr 16. pii: S0968-0004(26)00061-7. [Epub ahead of print]

Molecular mechanisms of PINK1/Parkin-mediated mitochondrial quality control.

Andrew N Bayne, Jean-François Trempe.

  PINK1/Parkin-mediated mitophagy and other related mitochondrial quality control pathways are critical to maintaining cellular homeostasis and neuronal health, and indeed, mutations in PINK1 and PRKN that disrupt this pathway cause early-onset Parkinson's disease. While PINK1-dependent Parkin recruitment to damaged mitochondria has been established for over a decade, recent structural and biochemical advances have illuminated the mechanisms governing their allosteric activation and integration into broader cellular signaling networks. This review synthesizes these insights, focusing on the molecular determinants of PINK1/Parkin activation and the regulatory crosstalk that integrates mitophagy with other cellular stress responses. These mechanistic advances position the PINK1/Parkin pathway as a promising, tractable therapeutic target for Parkinson's disease and related pathologies.

Keywords:  PINK1; Parkin; Parkinson’s disease; mitochondrial quality control (MQC); mitophagy; stress response; therapeutic development

DOI:  https://doi.org/10.1016/j.tibs.2026.02.014
Nat Rev Nephrol. 2026 Apr 14.

Therapeutic and mechanistic insights on mitochondrial transplantation in kidney disease.

James D McCully, Aybuke Celik, Amish Asthana, Giuseppe Orlando.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are major contributors to global morbidity and mortality, with limited treatment options beyond supportive care. Mitochondrial dysfunction is a shared feature of both conditions, driving impaired energy production, oxidative stress and cell death. Owing to its reliance on oxidative phosphorylation, the kidney is especially vulnerable to ischaemia-reperfusion injury, a leading cause of AKI and a risk factor for long-term loss of kidney function. Persistent mitochondrial damage contributes to the transition from AKI to CKD, and strategies aimed at restoring mitochondrial health, therefore, have therapeutic potential. Here, we focus on mitochondrial transplantation, a therapeutic approach that delivers viable, respiratory-competent mitochondria to injured tissue to support recovery. Mitochondria for transplantation can be isolated from a variety of sources (autologous or allogeneic) without triggering an immune, autoimmune or inflammatory response, or a reaction to damage-associated molecular patterns. Isolated mitochondria can be delivered by intra-arterial injection, and, once in the target organ, they are rapidly integrated into the cells through endocytosis. Mitochondrial transplantation supports the restoration of mitochondrial function and associated signalling pathways, promoting enhanced organ function and cellular viability. Several preclinical studies have demonstrated improved kidney function, reduced inflammation and preserved mitochondrial structure following mitochondrial therapy in models of ischaemia.

DOI: https://doi.org/10.1038/s41581-026-01072-2
BMC Pregnancy Childbirth. 2026 Apr 17.

Cesarean delivery in a pregnant woman with Ellis-van Creveld syndrome: a case report.

Yuwen Yu, Wenming Zhuang.



Keywords:  Case report; Cesarean delivery; Ellis-van Creveld syndrome; Pregnancy; Rare diseases

DOI:  https://doi.org/10.1186/s12884-026-09092-3
Adv Sci (Weinh). 2026 Apr 14. e23931

Mitochondrial Enzymes Mimetic Ultrasmall Palladium Nanozymes Prevent Senescence and Neurodegeneration Through Metabolic Reprogramming.

Wenshu Cong, Haiming Jing, Zinan Li, Wenjing Zhang, Nan Zhang, Yingqiu Xie, Shan Gao, Yuanyu Huang, Junyu Ning.

  Nanomaterials have been widely used to scavenge reactive oxygen species (ROS) and relieve mitochondria oxidative damage. However, developing nanomedicines that not only remove ROS but also accelerate the repair of dysfunctional mitochondria remains challenging. This study identifies polyvinylpyrrolidone (PVP)-modified palladium nanoparticles (PdP NPs) as mimics of cytochrome c oxidase (CcO) and superoxide dismutase (SOD), showcasing their potential as multifunctional nanoreactors to activate mitochondria for aging alleviation and neuroprotection. PdP NPs treatment enhances mitochondrial respiratory chain function, scavenges excessive ROS, thus alleviates cellular energy scarcity of aging individuals. Additionally, PdP NPs improve mitochondrial dynamics, promote biogenesis, and induce mitochondrial unfolded protein response (UPRmt), strengthening mitochondrial integrity and homeostasis for better therapeutic outcomes. In vivo evaluations reveal significant anti-aging effects, with the nanozymes notably reducing neurodegeneration and improving neuronal survival. This work highlights PdP NPs as a multifunctional nanotherapeutic platform capable of rewiring mitochondrial metabolism and homeostasis, offering a promising strategy for aging-related disease management.

Keywords:  aging; mitochondria; nanozyme; palladium nanoparticles; reactive oxygen species

DOI:  https://doi.org/10.1002/advs.202523931
Anesthesiology. 2026 Apr 17.

Ancient Mitochondrial Genetic Variant, Modern-day Pandora's Box.

Richard J Levy, Phil G Morgan.

DOI: https://doi.org/10.1097/ALN.0000000000006030
CNS Neurosci Ther. 2026 Apr;32(4): e70873

The Roles of Macrophage Lineage Cells (MLCs) in Brain Aging.

Qin Qin, Liubin Zhang, Manning Guo, Danli Lu, Yuxin Liu, Zihong Wang, Mengyan Hu, Shisi Wang, Xinmei Kang, Haotong Yi, Wei Qiu, Zhengqi Lu, Wei Cai.

   BACKGROUND: Brain aging poses a major public health challenge and is the primary risk factor for neurodegenerative diseases. Macrophage lineage cells (MLCs) have emerged as pivotal mediators of brain aging. While fundamental to central nervous system (CNS) homeostasis through their scavenging, detoxification, and neurotrophic functions, their transition to a senescent state is a primary driver of pathology. This shift is marked by a loss of clearance capacity and the adoption of a pro-inflammatory senescence-associated secretory phenotype (SASP).
OBJECTIVES: Here, we summarize the distinct and cooperative roles of MLC subsets in brain aging. We examine the key molecular drivers of MLCs senescence and detail how subset-specific dysfunction contributes to the propagation of cellular aging and related neuropathology. Finally, we evaluate current and emerging therapeutic strategies that target MLCs senescence.
CONCLUSION: We conclude by proposing a multidimensional management framework for brain aging. This framework positions MLCs as a central therapeutic hub, integrating advanced diagnostics and stratified interventions to preserve brain health and mitigate neurodegenerative pathology.

Keywords:  border‐associated macrophage; brain aging; microglia; monocyte‐derived macrophage

DOI:  https://doi.org/10.1002/cns.70873
bioRxiv. 2026 Apr 07. pii: 2026.04.05.716515. [Epub ahead of print]

Sulfide:quinone oxidoreductase drives mitochondrial supersulfide metabolism to regulate bioenergetics and longevity in eukaryotes.

Jia Yao, Tetsuro Matsunaga, Akira Nishimura, Meg Shieh, Tomoaki Ida, Minkyung Jung, Seiryo Ogata, Tsuyoshi Takata, Uladzimir Barayeu, Hozumi Motohashi, Masanobu Morita, Takaaki Akaike.

Sulfide:quinone oxidoreductase (SQR) is a critical enzyme that maintains sulfur metabolism by oxidizing sulfide to supersulfides, currently defined as sulfur metabolites with six valence electrons and no charge that are covalently catenated with other sulfur atoms and excludes disulfides. While SQR is known to contribute to mitochondrial electron transport, its physiological impact on systemic energy metabolism and longevity remains largely undefined. In this study, we investigated the role of SQR in mitochondrial bioenergetics and aging using SQR-deficient Schizosaccharomyces pombe ( Δhmt2 ) and a mitochondria-selective SQR-deficient ( Sqrdl ΔN/ΔN ) mice model. Functional analysis demonstrated that Δhmt2 grew normally in glucose but not in glycerol, indicating impaired mitochondrial respiration. It showed reduced membrane potential, ATP, and lifespan. Consistent with the yeast findings, Sqrdl ΔN/ΔN mice exhibited accumulated levels of hydrogen sulfide and persulfides, and demonstrated impaired mitochondrial energy metabolism. Furthermore, supersulfide donor supplementation selectively conferred lifespan extension in wild-type yeast, but not in SQR-deficient strain, and similarly improved mitochondrial function exclusively in wild-type mouse embryonic fibroblasts, with no benefit observed in SQR-mutant counterparts. Together, our findings demonstrate that mitochondrial SQR plays an essential role in sulfur respiration, critically supporting mitochondrial function and organismal longevity across eukaryotes.
Graphic Abstract:
Highlights: Developed an SQR-deficient S. pombe ( Δhmt2 ) model that exhibits sulfur metabolism, mitochondrial dysfunction, and shortened chronological lifespan Sulfide and supersulfide donors prolong yeast lifespan in a SQR-dependent mannerMitochondrial SQR is essential for membrane potential formation and ATP production in yeast and mammals.

DOI: https://doi.org/10.64898/2026.04.05.716515
bioRxiv. 2026 Apr 07. pii: 2026.04.04.716514. [Epub ahead of print]

Tau-induced mitochondrial reverse electron transport drives neurodegeneration.

Wen Li, Suman Rimal, Sunil Bhurtel, Lucas Yeung, Benjamin G Lu, Lea T Grinberg, Salvatore Spina, Maria Inmaculada Cobos Sillero, William W Seeley, Su Guo, Bingwei Lu.

Hyperphosphorylation and aggregation of the microtubule-associated protein tau are recognized as pathological hallmarks of tauopathies; however, the biological activity of tau that drives its pathophysiological effects remains poorly understood 1-6 . Mitochondrial dysfunction is a common feature of tauopathies 7,8 . Despite this, the mechanistic link between tau abnormalities and mitochondrial dysfunction, as well as its relationship to tau's physiological function, remains unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess ROS, reduces the NAD + /NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cells (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers significant stress resistance. Mechanistically, tau enters mitochondria and directly interacts with the mitochondrial complex I (C-I) subunit NDUFS3, enhancing RET activation in a phosphorylation-dependent manner that correlates with tau pathogenicity. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Blocking tau entry into mitochondria or disrupting tau/NDUFS3 interaction reduces tau-induced RET. Genetic or pharmacological inhibition of RET protects against tau-induced neurodegeneration across species. RET regulation represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for conditions characterized by tau abnormalities and mitochondrial dysfunction.

DOI: https://doi.org/10.64898/2026.04.04.716514
Nanomedicine (Lond). 2026 Apr 12. 1-6

Current challenges in the development of liposomes to target mitochondria.

Shrey Shah, Gerard G M D'Souza.

  Although liposomes have been shown to be capable of mediating the delivery of therapeutics to mitochondria, clinical translation has yet to be realized. This short, focused review outlines some major challenges and offers hypotheses that warrant systematic investigation to support the continued development of mitochondria targeted liposomal systems. An improved understanding of how surface chemistry, ligand density, and intracellular trafficking influence delivery efficiency and safety is crucial moving forward.

Keywords:  Liposomes; mitochondria; mitochondriotropics; nanomedicine; triphenylphosphonium

DOI:  https://doi.org/10.1080/17435889.2026.2658583
Int J Mol Sci. 2026 Mar 31. pii: 3161. [Epub ahead of print]27(7):

Mini-Galaxy: Rethinking Complex Human Diseases Through the Lens of Systems Biology and Multilayered AI Network Perspectives.

Cristina Correia, Choong Yong Ung, Zhuofei Zhang, Easton Blissenbach, Shizhen Zhu, Daniel D Billadeau, Yuin-Han Loh, Hu Li.

  Human diseases are complex and arise from the coordinated action of multiple genes and their protein products. Genes' behaviors extend beyond genetic variants, mutations, and differential expressions. Their coordinated activity across biological scales (molecules, cells, tissues, organs) produces emergent behaviors that shape health and disease. These emergent behaviors span time and space and are often hard to measure directly from observation when using standard experimental measurements. Yet these "hidden" or latent gene characteristics can be powerful drivers of disease. We propose a Mini-Galaxy Model (MGM), a systems-level AI-driven network framework that models cells as "mini-galaxies" composed of multilayered biological information, with each layer encoding a different dimension of genes' behavior. Here, we delineate a strategy on how to construct and compare MGMs across health and disease and map their etiological relatedness. We also operationalize the MGM as a discovery platform for translational medicine, offering modules to allow target prioritization and editing. By reframing human diseases as the result of emergent behavior of multilayered multimode biological networks and their perturbations, the MGM yields actionable rules to streamline biomarker discovery, guide target selection and enable rational design of combinatorial interventions, and accelerate drug repurposing.

Keywords:  artificial intelligence; latent gene properties; network; salient gene properties; systems biology

DOI:  https://doi.org/10.3390/ijms27073161
bioRxiv. 2026 Apr 07. pii: 2026.04.04.716517. [Epub ahead of print]

MitoChontrol: Adaptive mitochondrial filtering for robust single-cell RNA sequencing quality control.

Caitlin Strassburg, Danielle Pitlor, Aatur D Singhi, Rachel A Gottschalk, Shikhar Uttam.

Summary: Mitochondrial transcript abundance is a standard quality control metric in single-cell RNA sequencing, but fixed percentage thresholds fail to account for the substantial variation in mitochondrial content across cell types and tissues, risking both retention of compromised cells and exclusion of transcriptionally active viable cell populations. We present MitoChontrol, a cell-type-aware probabilistic framework for mitochondrial quality control that models the mitochondrial transcript fraction within transcriptionally coherent clusters as a Gaussian mixture distribution. Compromised-cell components are identified from the upper tail of each cluster-specific distribution, and filtering thresholds are defined as the point at which the posterior probability of cellular compromise exceeds a user-definded confidence value. Applied to controlled perturbation experiments and a pancreatic ductal adenocarcinoma single-cell dataset, MitoChontrol selectively removes transcriptionally compromised cells while preserving biologically elevated but viable populations, outperforming fixed-threshold and outlier-based approaches.
Availability and Implementation: MitoChontrol is implemented in Python and integrates directly with AnnData-based workflows. It is freely available under the GNU General Public License v3 (GPL-3.0) at: https://github.com/uttamLab/MitoChontrol (DOI: https://doi.org/10.5281/zenodo.19423054 ).

DOI: https://doi.org/10.64898/2026.04.04.716517
Int J Health Policy Manag. 2025 ;pii: 8916. [Epub ahead of print]14 8916

Orphan Drug Approval in Canada, 1999-2022: A Cross-sectional Study.

Joel Lexchin.

  The number of drugs for orphan indications has been increasing significantly in Canada and the federal government recently announced an investment of $1.5 billion dollars over 3 years primarily directed at helping to fund the cost of these drugs. There are claims and counterclaims about what percent of Food and Drug Administration (FDA) orphan drugs are available in Canada and how delayed these drugs are in being approved by Health Canada. This study uses FDA and Health Canada databases and data from three health technology assessment agencies and one drug bulletin to provide objective data about the percent of FDA approved drugs that were also approved by Health Canada, any delays in Canadian approval and the additional therapeutic value of new orphan drugs. Decisions about what drugs should be publicly covered and how long it took to make those decisions were not investigated. From 1999 to 2022, the FDA approved 326 new drugs for an orphan indication and Health Canada approved 231 (70.9%) for the same indication. The median time between FDA and Health Canada approval was 346 days (interquartile range [IQR] 181, 785). The percent rated as major improvements declined from 50% of the total in 2004-2008 to 13.6% in 2019-2022. These findings need to be taken into account as Canada develops an orphan drug policy and decides on criteria for funding this group of drugs. Specifically, when high quality evidence about the additional therapeutic value of orphan drugs is not available at the time of approval, risk sharing funding agreements with manufacturers should be put in place. Manufacturers should understand that if the results of post-market trials do not provide convincing evidence of value, funding will be withdrawn. Finally, the quality of any research plan should be used to prioritize candidates for federal funding.

Keywords:  Drug Approval; Food and Drug Administration; Health Canada; Orphan Drugs; Therapeutic Class; Therapeutic Value

DOI:  https://doi.org/10.34172/ijhpm.8916
Neural Regen Res. 2026 Apr 14.

Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.

Valentina Tedeschi, Raffaella Ciancio, Silvia Piccirillo, Alessandra Preziuso, Tiziano Serfilippi, Valentina Terenzi, Simona Magi, Vincenzo Lariccia, Pasqualina Castaldo, Antonio Vinciguerra, Ilaria Piccialli, Lorella Maria Teresa Canzoniero, Anna Pannaccione, Agnese Secondo.

  Several lines of evidence suggest that targeting dysfunctional calcium (Ca2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca2+ efflux or modulate mitochondrial Ca2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.

Keywords:  ; autophagy; channels; endoplasmic reticulum; endoplasmic reticulum stress; lysosome; mitochondria; mitochondria-associated membranes; neurodegenerative diseases

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01754
Stem Cells. 2026 Apr 09. pii: sxag019. [Epub ahead of print]

Stem cells enhance mitochondrial function in experimental Huntington's disease.

Francesco D'Egidio, Napasiri Putthanbut, Michaela Starahs, Jea Young Lee, Cesario V Borlongan.

  Huntington's Disease (HD) is a neurodegenerative disorder caused by CAG triplet expansion in the HTT gene, producing a mutant Huntingtin protein that impairs mitochondrial dynamics by reducing fusion and increasing fission. Mesenchymal stem cells (MSCs) have shown potential therapeutic effects by sharing functional mitochondria and other secretomes. In this study, quinolinic acid-lesioned neuro-2a (QA-N2a) cells and glutamatergic neurons with 50 CAG repeats (HD neurons) were co-cultured with human umbilical cord-derived MSCs for 5 hours. For QA-N2a cells, immunocytochemistry was performed to demonstrate change in GABA and Substance P before and after co-culture. For HD neurons, immunocytochemistry was conducted to identify mitochondrial proteins, while Western Blot was employed to evaluate proteins related to inflammation and mitochondrial function. As a result, co-culture with MSC significantly restored the expression of GABA and Substance P, which diminished after QA exposure. In HD neurons co-cultured with MSCs, an increase in mitochondrial abundance was observed, with significantly higher intensity and dendritic distribution of mitochondria compared to control cells. Western Blot analysis confirmed this increase and showed a rising trend in ATP5a levels. MSCs also promoted mitochondrial fusion, indicated by higher levels of Mitofusin 2 (MFN2) and Mitochondrial Dynamin Like GTPase (OPA1), and a trend of reduction in the fission marker Dynamin-Related Protein (DRP1). Additionally, the co-culture led to a decreased trend in neuroinflammation markers IL-6, TNF-α, MMP9, and p-NFkB. Collectively, this study demonstrates that MSCs alleviate HD pathology by restoring mitochondria activity and potentially suppressing inflammation in two different HD in vitro models.

Keywords:  Huntington’s disease; cell-free therapy; mesenchymal stem cells; mitochondrial transfer; secretome

DOI:  https://doi.org/10.1093/stmcls/sxag019
Geriatr Gerontol Int. 2026 Apr;26(4): e70484

Association of Mitochondrial DNA Levels in Peripheral Blood Leukocytes With Physical Performance in Older Adults.

Hiroaki Ikezaki, Ryoko Nakashima, Hideyuki Nomura, Nobuyuki Shimono.

   BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) in peripheral blood leukocytes has emerged as a surrogate marker of mitochondrial function. This study examined associations between leukocyte mtDNA-CN, physical performance, and lipid metabolism in community-dwelling older adults.
METHODS: We conducted a cross-sectional analysis of 594 adults aged ≥ 50 years (median 71 years; 351 women, 243 men) who were independent in activities of daily living. Physical performance was assessed using handgrip strength and gait parameters measured with a triaxial accelerometer. Frailty status was evaluated using the Japanese version of the Cardiovascular Health Study (J-CHS) criteria. Blood samples were collected after fasting for mtDNA-CN and other blood chemical measurements.
RESULTS: Median values of mtDNA-CN were 124 in women and 114 in men. According to the J-CHS criteria, 6.1% of women and 6.3% of men were classified as frail, while 48.9% of women and 53.6% of men were pre-frail. Participants with higher mtDNA-CN levels demonstrated superior physical performance. After multivariable adjustment, mtDNA-CN correlated positively with gate ability in women and handgrip strength in men. In addition, mtDNA-CN correlated positively with iron in women and high-density lipoprotein cholesterol (HDL-C) in men, and negatively with uric acid and C-reactive protein in men. In the multivariate regression analyses, mtDNA-CN still showed positive associations with handgrip strength and HDL-C, a negative association with uric acid in men, and a positive association with iron in women and men.
CONCLUSION: Leukocyte mtDNA-CN was associated with physical performance, suggesting its potential utility as a biomarker for frailty assessment in older adults.

Keywords:  frailty; gait speed; handgrip; mitochondrial DNA; triglycerides

DOI:  https://doi.org/10.1111/ggi.70484
J Biomed Inform. 2026 Apr 11. pii: S1532-0464(26)00063-8. [Epub ahead of print] 105039

Learning to take it personally: Precision drug repurposing through patient-specific loss on knowledge graphs using Biobank data.

Çerağ Oğuztüzün, Zhenxiang Gao, Jing Li, Xin Qi, Mehmet Koyutürk, Rong Xu.

   OBJECTIVE: Precision medicine requires drug repurposing methods that adapt to individual patient profiles while working within regulatory frameworks. Existing approaches apply uniform models to all patients, only using individual factors as inputs or filters.
METHODS: Our framework instead integrates patient-specific profiles into the learning algorithm through a customized loss function. We combine standard link prediction with UK Biobank data-integrating polygenic risk scores, biomarker expressions, and medical history.
RESULTS: Evaluated on a biomedical knowledge graph connecting 61,000+ entities through 1.2+ million relations, our approach improves drug repurposing quality with AUPRC improvements ranging from 1.3× to 5.4× across patients. Case studies on Alzheimer's Disease patients reveal drug candidates with stronger AD evidence and patient-specific mechanisms. Our loss function identifies influential diseases and biomarkers for each patient, enhancing interpretability while providing biologically relevant recommendations tailored to individual profiles.
CONCLUSION: This approach represents a fundamental shift from treating personalization as data preprocessing to embedding it within the learning objective itself.

Keywords:  Drug repurposing; Graph machine learning; Knowledge graphs; Precision drug repurposing; Precision medicine

DOI:  https://doi.org/10.1016/j.jbi.2026.105039