bims-ripira 2026-06-28 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2026–06–28
eighteen papers selected by
Martín Lopo

Nicotinamide riboside reduces glial inflammation and boosts mitochondrial function.
Curcumin Protects SDH2 Mutant from Oxidative Stress and Improves Mitochondrial Function: Application Potential for Complex II Deficiency.
Mitochondrial Dysfunction in Autism and Attention-Deficit/Hyperactivity Disorder: Evidence from Genetic, Biochemical, and Neuroimaging Approaches.
Electroconvulsive Treatment for Depression Alters Mitochondrial Serum Metabolites.
Norepinephrine regulates hippocampal mitochondrial biogenesis via β2-adrenergic receptor signaling and PGC-1α.
Activity of DNA- and RNA-Guided Prokaryotic Argonautes in Human Mitochondria.
Ginkgo Biloba Extract Ameliorates Age-Related Mitochondrial Deficits in Human iPSCs and Their Derived Neurons and Astrocytes.
Elucidation of Brain Morphogenesis Using Quantitative Brain Magnetic Resonance Imaging in Children.
Urolithin A improves mitochondrial dysfunction induced by oxidative stress in human dermal papilla cells.
Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.
Paradoxical hypolibido in a hyperandrogenic male with POLG-related mitochondrial disease.
Multi-ancestry analysis of POLG variants in Parkinson's disease.
Jianpi Qiangji granules improve muscle function in sarcopenia and reshape bile acid metabolism: A randomized double-blind positive-controlled trial.
The Pyruvate Dehydrogenase Complex: A 90-Year-Old Enigma Shaping the Future of Structural Enzymology.
Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.
CIRBP maintains skeletal muscle mitochondrial energy homeostasis via mt-ATP6 to ameliorate sarcopenia.
Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
Screening and Stratification Utility of GDF-15 and FGF-21 in Individuals Evaluated for Suspected Mitochondrial Disease: A Malaysian Cohort Study.

Int J Biol Sci. 2026 ;22(11): 6035-6063

Nicotinamide riboside reduces glial inflammation and boosts mitochondrial function.

Tsering Yangzom, Anbin Chen, Bjørn Christian Lundberg, Kristina Xiao Liang.

Astrocyte dysfunction plays a pivotal role in the pathogenesis of POLG-related mitochondrial diseases, yet the underlying mechanisms remain poorly understood. Here, we employed human iPSC-derived astrocytes, cortical organoids and astrocyte-neuron co-culture systems to model POLG mutations and investigate astrocyte-mediated neurotoxicity. Single-cell transcriptomic profiling revealed a marked expansion of A1 neurotoxic astrocytes, depletion of A2 neuroprotective astrocytes, and reduction of neuronal populations in POLG organoids. A1 astrocytes exhibited transcriptional signatures of mitochondrial dysfunction, inflammatory signaling (TGF-β, JAK-STAT), impaired neuro-supportive functions, and activation of senescence, autophagy, and proteostasis stress pathways. Co-cultured dopaminergic neurons displayed impaired morphology and widespread transcriptional downregulation of mitotic, cytoskeletal, and synaptic genes, along with activation of inflammatory and ion transport pathways. Treatment with the NAD⁺ precursor nicotinamide riboside (NR) attenuated astrocyte reactivity, reduced IL-6 and CXCL1 secretion, improved neuronal structure and synaptic marker expression, and increased mtDNA copy number and ATP production in POLG astrocytes. Our study identifies NAD⁺ augmentation as a promising strategy to mitigate astrocyte-driven pathology in mitochondrial encephalopathies.

DOI: https://doi.org/10.7150/ijbs.119262
Int J Mol Sci. 2026 Jun 10. pii: 5253. [Epub ahead of print]27(12):

Curcumin Protects SDH2 Mutant from Oxidative Stress and Improves Mitochondrial Function: Application Potential for Complex II Deficiency.

Yi Liu, Na Wang, Heng Cai.

  Complex II deficiency is a rare inherited mitochondrial disorder characterized by structural and functional deficiency of complex II, for which there is currently no definitive drug treatment. Curcumin is a polyphenolic compound with antioxidant, anti-inflammatory, anti-tumor, and anti-aging properties. By constructing a mutant strain of the Saccharomyces cerevisiaeSDH2 gene, we can mimic the functional defects of Complex II caused by human SDHB mutations, and then explore the ameliorative effect of curcumin on Complex II functional defects. Cell viability was assessed using MTT and CFU. Antioxidant capacity was evaluated by measuring DCFH-DA and antioxidant enzyme activity, while the expression levels of respiratory chain-related genes were detected by qRT-PCR. Experimental results demonstrate that curcumin can restore cell growth and viability, scavenge ROS from cells as well as positively regulate mitochondrial function; however, the above results are regulated by the concentration of curcumin. In conclusion, these findings provide experimental support for curcumin as a preliminary intervention for Complex II deficiency and other mitochondrial diseases, further enriching the evidence for the potential application of curcumin in mitochondrial-related diseases.

Keywords:  complex II deficiency; curcumin; mitochondrial disorders; oxidative stress

DOI:  https://doi.org/10.3390/ijms27125253
Antioxidants (Basel). 2026 Jun 18. pii: 764. [Epub ahead of print]15(6):

Mitochondrial Dysfunction in Autism and Attention-Deficit/Hyperactivity Disorder: Evidence from Genetic, Biochemical, and Neuroimaging Approaches.

Tina R Ram, Chunlong Mu, Sarah J MacEachern, Jane Shearer.

  Mitochondrial dysfunction has been increasingly implicated in the pathobiology of neurodevelopmental conditions, particularly autism and attention-deficit/hyperactivity disorder (ADHD). Because the developing brain is critically dependent on sustained ATP production, impairments in oxidative phosphorylation, mitochondrial dynamics, and redox balance may disrupt neuronal maturation, synaptic development, and neural circuit refinement during sensitive developmental periods. This review examines evidence from postmortem neurochemistry, genomics, magnetic resonance spectroscopy, and biomarker research to characterize mitochondrial impairment across autism and ADHD. Studies in autism report an elevated burden of heteroplasmic mitochondrial DNA (mtDNA) variants, along with alterations in mtDNA copy number, respiratory chain capacity, fission-fusion dynamics, and antioxidant defenses. Postmortem data demonstrate reduced activity of electron transport chain Complexes I, III, and V in the frontal cortex, temporal lobe, and cerebellum. These bioenergetic abnormalities are accompanied by elevated oxidative stress markers alongside mitochondria-mediated immune activation. In vivo neuroimaging corroborates these findings through elevated cerebral lactate and reduced phosphocreatine-to-ATP ratios. Evidence in ADHD is limited, but similarly implicates mitochondrial dysfunction, consistent with the frequent co-occurrence of these conditions and their partially shared architecture. The available literature supports mitochondrial dysfunction as a transdiagnostic biological feature of neurodevelopmental conditions, with relevance to mechanistic biomarker identification and targeted therapeutic development.

Keywords:  bioenergetics; electron transport chain; energy; metabolism; mitochondria; neurodevelopment; neuroinflammation; oxidative stress; phenotype

DOI:  https://doi.org/10.3390/antiox15060764
Biol Psychiatry Glob Open Sci. 2026 Sep;6(5): 100754

Electroconvulsive Treatment for Depression Alters Mitochondrial Serum Metabolites.

Erik Pålsson, Robert Sigström, Alireza Salehi, Mattias Hedenström, Axel Nordenskjöld, Mikael Landén.

   Background: Electroconvulsive therapy (ECT) is the most effective treatment for severe and treatment-resistant depression, but its biological mechanisms remain poorly understood. Given the pivotal role of mitochondria in cellular energy metabolism and their proposed involvement in the pathology of depression, we aimed to investigate whether ECT alters mitochondrial metabolism.
Methods: We included 102 patients with major depressive disorder referred for ECT at 7 Swedish hospitals. Fasting serum samples were collected at 3 time points: immediately before the first ECT session (T0), 30 minutes after the first session (T1), and before the sixth session (T2). Proton nuclear magnetic resonance spectroscopy was used to quantify metabolites related to the tricarboxylic acid cycle and amino acid metabolism.
Results: Acutely (T0→T1), serum levels of citrate, glucose, glutamine, and pyruvate increased significantly, while formate and phenylalanine decreased. Across the treatment course (T0→T2), alanine and pyruvate levels increased, whereas the ketone bodies acetoacetate, acetone, and 3-hydroxybutyrate decreased significantly. An exploratory analysis indicated that the reduction in ketone bodies (T0→T2) was confined to patients showing clinical improvement, as defined by the Clinical Global Impressions-Improvement scale.
Conclusions: ECT induces both acute and sustained alterations in mitochondrial energy metabolism. These findings suggest that ECT modulates systemic mitochondrial function, warranting further investigation into how these metabolic changes relate to clinical improvement.

Keywords:  Clinical study; Electroconvulsive treatment; Energy metabolism; Major depression; Metabolomics

DOI:  https://doi.org/10.1016/j.bpsgos.2026.100754
Neuropsychopharmacology. 2026 Jun 25.

Norepinephrine regulates hippocampal mitochondrial biogenesis via β2-adrenergic receptor signaling and PGC-1α.

Darshana Kapri, Amogh Bhaskaran Jayaprasad, Praachi Tiwari, Mukund Sharma, Angarika Balakrishnan, Aastha Singla, Ishanee Mazumder, Ullas Kolthur-Seetharam, Sashaina E Fanibunda, Ashok D B Vaidya, Vidita A Vaidya.

Neuronal mitochondria are central to not only maintaining cellular bioenergetics, calcium dynamics, and serving as signaling platforms, but are also critical for specialized functions including synaptic plasticity and neurotransmission. While mitochondria are postulated to have a fundamental role in the functioning of neurons, it is only recently that upstream factors that influence mitochondria in neurons have been systematically investigated. Here, we identify the critical role of the neurotransmitter, norepinephrine (NE) in modulating mitochondria in the rodent hippocampus. NE increases the expression of key regulators of mitochondrial biogenesis (SIRT1 and PGC-1α), enhances mitochondrial DNA content and ATP levels in hippocampal neurons in culture. These effects of NE are mediated via the recruitment of a β2-adrenergic receptor-Gs-cAMP-PKA signaling cascade and are dependent on PGC-1α. We find that increasing noradrenergic signaling in vivo, either through direct administration of NE into the hippocampus via osmotic minipumps or treatment with the NE reuptake inhibitor, Atomoxetine, as well administration of the β2-adrenergic receptor agonist, Formoterol, enhances mitochondrial DNA content in the hippocampus. Furthermore, increased spatial memory recall with Atomoxetine treatment was significantly correlated with both mitochondrial DNA content and ATP levels in the hippocampus. Our findings identify a novel role for NE in impacting mitochondrial biogenesis in the hippocampus, and suggest a link between bioenergetic status and spatial memory performance.

DOI: https://doi.org/10.1038/s41386-026-02470-7
Cells. 2026 Jun 22. pii: 1129. [Epub ahead of print]15(12):

Activity of DNA- and RNA-Guided Prokaryotic Argonautes in Human Mitochondria.

Beatrisa Rimskaya, Ekaterina Kropocheva, Iaroslava Ponomareva, Lada Karchemkina, Lidiya Lisitskaya, Daria Gelfenbein, Egor Ulashchik, Vadim Shmanai, Andrey Kulbachinskiy, Ilya Mazunin.

  Precise manipulation of mitochondrial DNA (mtDNA) by CRISPR-Cas systems remains challenging, largely due to inefficient import of guide RNAs, motivating the exploration of alternative programmable nucleases. Here, we show that prokaryotic Argonaute nucleases (pAgos) of various classes can be efficiently targeted to human mitochondria. Using the Su9 mitochondrial targeting sequence from Neurospora crassa, we achieved robust mitochondrial import of four pAgos-DecAgo, CbuAgo, KmaAgo and RslAgo. As a functional readout of their activity in cells, we targeted the single-stranded D-loop region, which plays a central role in mtDNA replication and maintenance, reasoning that cleavage at this site was expected to potentially result in a reduction in mtDNA copy number. Of the four enzymes, only RNA-guided DecAgo induced a pronounced reduction in mtDNA levels, decreasing copy number approximately fivefold within 48 h. Unexpectedly, this effect occurred independently of exogenous guides, suggesting that DecAgo may utilize endogenous mitochondrial guide RNAs. These findings identify DecAgo as an active nuclease in human mitochondria and reveal a previously unrecognized mode of targeting, highlighting the need to further investigate the underlying mechanism and the potential role of endogenous guide molecules, as well as improving targeting specificity.

Keywords:  D-loop; mitochondria; mtDNA copy number; prokaryotic argonautes

DOI:  https://doi.org/10.3390/cells15121129
Antioxidants (Basel). 2026 May 29. pii: 689. [Epub ahead of print]15(6):

Ginkgo Biloba Extract Ameliorates Age-Related Mitochondrial Deficits in Human iPSCs and Their Derived Neurons and Astrocytes.

Imane Lejri, Amandine Grimm, Anne Eckert.

  Mitochondrial dysfunction is a central feature of aging, driving bioenergetic decline, increased oxidative stress, and increased vulnerability to neurodegenerative diseases. Human induced pluripotent stem cells (iPSCs) and iPSC-derived neurons provide powerful models to study these processes. Ginkgo biloba extract GBE LI1370 (GBE) has demonstrated antioxidant and mitochondria-protective properties in preclinical models, including improvements in mitochondrial membrane potential, reduction in reactive oxygen species, and enhanced neuronal survival. However, its effects on mitochondrial function in human iPSCs and their differentiated derivatives in the context of aging have not yet been investigated. This study evaluated the mitochondrial protective effects of GBE (100 µg/mL) in an established iPSC-based model of aging and in neurons and astrocytes derived from aged iPSCs. Mitochondrial parameters, including ATP production, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS), superoxide levels, and mitochondrial respiration, were assessed. Aged iPSCs exhibited reduced ATP production and MMP, together with increased mtROS and superoxide levels compared to young controls. Astrocytes derived from aged iPSCs also displayed mitochondrial dysfunction. Treatment with GBE for 24 h increased ATP production and MMP, reduced oxidative stress, and improved mitochondrial respiration in both young and aged iPSCs, as well as in aged iPSC-derived neurons and astrocytes. These preliminary donor-based findings support further investigation of GBE-associated mitochondrial responses in human donor-derived cellular models of aging and warrant validation in larger donor cohorts.

Keywords:  Ginkgo biloba extract; aging; bioenergetics; iPSC-derived astrocytes; iPSC-derived neurons; induced pluripotent stem cells (iPSCs); mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.3390/antiox15060689
Pediatr Int. 2026 Jan-Dec;68(1):68(1): e70450

Elucidation of Brain Morphogenesis Using Quantitative Brain Magnetic Resonance Imaging in Children.

Tadashi Shiohama.

  Quantitative brain magnetic resonance imaging has revolutionized pediatric neurodevelopment research by enabling noninvasive, reproducible, and high-resolution assessments of brain morphology across the entire brain. Advances in anatomical structure analysis and diffusion-weighted tractography now permit detailed characterization of gray and white matter, cortical thickness, surface area, gyrification, and fiber integrity throughout development. Automated processing pipelines, including FreeSurfer, FSL, and CIVET, have supported large-scale analyses, while harmonization frameworks and normative growth curves have facilitated clinical translation. Diffusion tensor imaging (DTI) provides complementary insights into white matter microstructure, revealing neurodevelopmental trajectories and disorder-specific connectivity alterations. These approaches have identified structural biomarkers in multiple conditions, including reduced nucleus accumbens volume and ventricular enlargement in autism spectrum disorder (ASD), as well as early amygdala overgrowth and glymphatic dysfunction that may predict ASD onset. Despite these advances, several challenges remain, such as inter-scanner variability, age-dependent processing limitations, and the lack of validated individual-level biomarkers. Standardization of imaging protocols and robust statistical harmonization will be essential to overcome these obstacles and enable longitudinal, patient-specific assessments. The incorporation of quantitative magnetic resonance imaging into clinical workflows holds promise for early diagnosis, individualized monitoring, and therapeutic stratification of neurodevelopmental and genetic disorders. Ultimately, comprehensive morphometric and diffusion-based profiling will advance understanding of brain morphogenesis and drive precision medicine in pediatric neurology.

Keywords:  autism spectrum disorder; brain morphology; diffusion magnetic resonance imaging; diffusion tensor imaging; harmonization

DOI:  https://doi.org/10.1111/ped.70450
BMB Rep. 2026 Jun 24. pii: 6620. [Epub ahead of print]

Urolithin A improves mitochondrial dysfunction induced by oxidative stress in human dermal papilla cells.

Iksun Kwon, Seo-Eun Lee, Yujin Kim, Shin-Hye Yu, Jeong Seon Yeo, Jeong-Wook Hwang, Chung Sub Han, Kyuboem Han, Chun-Hyung Kim, Young Cheol Kang.

Hair loss is a psychologically debilitating condition affecting social interactions. Despite extensive research, current interventions are transient and provide limited efficacy. Emerging evidence highlights that oxidative stress, resulting from mitochondrial dysfunction, impairs hair growth and disrupts hair cycle regulation. Urolithin A (UA), known to enhance mitochondrial function via mitophagy activation, has not yet been studied for its protective effects against hair loss. Here, we investigate whether UA protects against oxidative stress and promotes hair growth by restoring mitochondrial function in human dermal papilla cells (hDPCs) and clinical cases. hDPCs were subjected to H2O2 to induce oxidative stress and treated with various UA concentrations. Protective effects were assessed via mitochondrial function, morphology, apoptosis assays and Wnt/β-catenin signaling activity. Clinical evaluation involved measuring hair root volume and shedding rates following topical UA application. UA treatment improved mitochondrial function, reduced cell death under oxidative stress conditions, and activated Wnt/β-catenin signaling by increasing Wnt and β-catenin expression in hDPCs. Clinically, UA application led to increased hair root volume and decreased hair shedding. These dual effects on mitochondrial function and Wnt/β-catenin signaling highlight the potential of UA as a novel intervention for hair loss management.
Biomed Pharmacother. 2026 Jun 26. pii: S0753-3322(26)00735-3. [Epub ahead of print]201 119699

Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.

Li-Tzu Wang, Han-Ying Jhuang.

  Clinical development for primary mitochondrial diseases (PMDs) has spanned more than two decades, yet therapeutic success remains limited. In this Review, we provide a comprehensive, pharmacology-focused analysis of the PMD clinical trial landscape and identify key mechanistic and translational determinants underlying recent progress. A systematic survey of ClinicalTrials.gov covering January 2010 to April 2026 identified 159 registered studies across PMD subtypes after deduplication, including 110 interventional trials. Progress has been constrained by marked genetic and phenotypic heterogeneity, small and geographically dispersed patient populations, and the lack of validated pharmacodynamic and disease-specific endpoints. Consequently, several well-designed late-stage trials have yielded negative or inconclusive outcomes, and regulatory approvals have historically been scarce. Recent advances, however, indicate a shift in trajectory. Four therapies have achieved regulatory authorization, including idebenone for Leber hereditary optic neuropathy, taurine for MELAS, and recent FDA approvals of doxecitine and doxribtimine (Kygevvi) for thymidine kinase 2 deficiency and elamipretide (FORZINITY) for Barth syndrome. These successes share a convergent translational framework integrating mechanism-based pharmacology, genotype-driven patient selection, and biologically aligned endpoints. Clinical activity has also accelerated, with approximately half of PMD interventional trials initiated since 2020 and 50 studies currently active or recruiting. Emerging strategies include NAD⁺ augmentation, soluble guanylate cyclase stimulation, mTOR modulation, gene therapies, and heteroplasmy-targeting approaches. Collectively, these advances mark an emerging inflection point and suggest a path toward greater regulatory success in the coming decade.

Keywords:  Clinical trials; Gene therapy; Leber hereditary optic neuropathy; MELAS; Primary mitochondrial disease; Translational medicine; Trial design

DOI:  https://doi.org/10.1016/j.biopha.2026.119699
J Sex Med. 2026 Jun 05. pii: qdag187. [Epub ahead of print]23(7):

Paradoxical hypolibido in a hyperandrogenic male with POLG-related mitochondrial disease.

Hector Rodrigo Gonzalez-Carranza, Luis Antonio Reyes-Vallejo.



Keywords:  hyperandrogenism; libido; mitochondrial diseases; testosterone

DOI:  https://doi.org/10.1093/jsxmed/qdag187
medRxiv. 2026 Jun 08. pii: 2026.06.07.26354811. [Epub ahead of print]

Multi-ancestry analysis of POLG variants in Parkinson's disease.

Global Parkinson’s Genetics Program (GP2)

Introduction: Variants in the polymerase gamma ( POLG) gene are associated with a wide range of mitochondrial disorders. Emerging evidence suggests a potential link between POLG variants and Parkinson's disease (PD); yet, results remain inconclusive.
Objectives: To investigate the genetic spectrum and prevalence of POLG variants in PD across diverse ancestries.
Methods: We leveraged multi-ancestry genetic data from the Global Parkinson's Genetics Program (GP2), including genotyping data from 98,589 and short-read sequencing data from 36,022 individuals. We performed a POLG rare variant screen, case-control association, and gene-level burden analyses.
Results: Five PD cases carried potentially biallelic rare pathogenic/likely pathogenic POLG variants. Additionally, 228 individuals (<1%; 161 PD cases, 28 individuals with other neurological disorders, and 39 controls) carried 34 distinct rare pathogenic/likely pathogenic heterozygous variants, with no significant frequency differences between cases and controls, except for the p.Ala467Thr variant in the European population. The co-inherited pathogenic variants p.Thr251Ile and p.Pro587Leu were present in <1% of both cases and controls, with no significant group differences. Burden and variant-level association analyses showed no association between rare POLG variant burden or common POLG variant enrichment and PD.
Conclusions: POLG variants are overall rare in PD. The identification of rare pathogenic variants among PD cases suggests that POLG -related mitochondrial dysfunction may contribute to PD in isolated instances, particularly under recessive inheritance. Our findings support a role for POLG variants in select cases and underscore the need for larger-scale sequencing and functional studies.

DOI: https://doi.org/10.64898/2026.06.07.26354811
Exp Gerontol. 2026 Jun 21. pii: S0531-5565(26)00190-7. [Epub ahead of print]222 113211

Jianpi Qiangji granules improve muscle function in sarcopenia and reshape bile acid metabolism: A randomized double-blind positive-controlled trial.

Yujie Zhang, Zhe Pan, Zhengyan Li, Haoyue Wang, Jiaqi Rong, Huamei Yan, Yunfan Zhan, Jingjing Zhang, Yushi Yao, Wei Liu, Weian Yuan.

   BACKGROUND: Jianpi Qiangji Granule (JQG), an in-hospital traditional Chinese medicine formulation developed at Shuguang Hospital, is clinically used for sarcopenia; however, high-quality evidence supporting its efficacy remains limited. Sarcopenia is an age-related condition characterized by progressive loss of skeletal muscle mass, strength, and physical function, substantially impairing quality of life in older adults. This exploratory trial aimed to evaluate the preliminary efficacy and safety of JQG in older patients with sarcopenia.
METHODS: Eighty patients with sarcopenia were randomly assigned to receive JQG or calcitriol for 12 weeks under a double-blind, double-dummy, positive-controlled design. The primary outcome was the change in grip strength from baseline to week 12. Secondary outcomes included skeletal muscle index (SMI), 6-meter walking speed, and Sarcopenia Quality of Life (SarQoL) scores. Additional serum biomarkers, including IL-1β, IL-6, IL-10, TNF-α, growth hormone, testosterone, brain-derived neurotrophic factor (BDNF), and growth differentiation factor 15 (GDF15) were evaluated. To explore potential metabolic mechanisms, untargeted serum metabolomics was performed, followed by pathway enrichment analysis and targeted bile acid profiling. Safety assessments included vital signs, routine laboratory tests, serum electrolytes including calcium, and adverse events.
RESULTS: In the intention-to-treat/full analysis set (ITT/FAS) analysis, JQG was associated with a greater improvement in the primary outcome, grip strength, than calcitriol after 12 weeks, with an adjusted between-group difference of 1.49 kg (95% CI: 0.24 to 2.75). For secondary outcomes, JQG showed greater improvements in 6-meter walking speed, with an adjusted between-group difference of 0.13 m/s (95% CI: 0.05 to 0.22), and SarQoL score, with an adjusted between-group difference of 8.13 points (95% CI: 4.15 to 12.11). The adjusted between-group difference in SMI was 0.03 kg/m2 (95% CI: -0.13 to 0.19). Exploratory biomarker analyses suggested treatment-associated changes in inflammatory, hormonal, neurotrophic, and aging-related markers. Both interventions were well tolerated, and no clinically significant hypercalcemia or major safety concern was observed. Untargeted serum metabolomics suggested treatment-associated metabolic remodeling, with pathway enrichment highlighting bile acid-related metabolism. Targeted bile acid profiling further indicated changes in circulating bile acid composition, including alterations in free, conjugated, primary, and secondary bile acid species, accompanied by increased serum FGF19 levels.
CONCLUSION: In this exploratory randomized trial, JQG was associated with greater improvements in grip strength, physical performance, and sarcopenia-related quality of life than calcitriol over 12 weeks, with no major safety concerns observed. Exploratory biomarker and metabolomic findings suggest that inflammatory regulation, hormonal and neurotrophic modulation, and bile acid-related metabolic remodeling may be involved in the response to JQG. These findings are hypothesis-generating and warrant confirmation in larger, multicenter, adequately powered trials.
TRIAL REGISTRATION: This trial was registered at the Chinese Clinical Trial Registry (ChiCTR) on October 21, 2024 (Registration No. ChiCTR2400091125).

Keywords:  Bile acids; Clinical study; FGF19; Jianpi Qiangji granules; Non–targeted metabolomics; Sarcopenia

DOI:  https://doi.org/10.1016/j.exger.2026.113211
Adv Exp Med Biol. 2026 ;1514 207-253

The Pyruvate Dehydrogenase Complex: A 90-Year-Old Enigma Shaping the Future of Structural Enzymology.

Toni K Träger, Fotis L Kyrilis, Greg Kafetzopoulos, Christian Tüting, Panagiotis L Kastritis.

  The ancient pyruvate dehydrogenase complex (PDHc) performs the "link reaction" of cellular respiration-a discovery from the 1930s that was central in the award of the 1953 Nobel Prize in Physiology and Medicine to Krebs and Lipmann. Fast forward to 2024, PDHc emerges with roles in Alzheimer's, cancer, and neurodegeneration, as well as in obesity and aging processes. Due to these recent reports, structural analysis of PDHc, a 10-megadalton enzymatic complex, comes into focus-only now this analysis begins to unveil an enormous and challenging molecular complexity. Cutting-edge techniques and methods, such as cryo-electron microscopy (cryo-EM), cross-linking (XL) and mass spectrometry (MS), advanced molecular and biochemical analysis, and computational structural biology, powered by artificial intelligence (AI), converge to systematically probe the mechanistic details governing PDHc function. This chapter collects and updates the knowledge in PDHc structure and function and pinpoints unresolved questions, with the hope of not waiting another 90 years for their answer.

Keywords:  Acetyl-CoA; Citric acid cycle; Enzyme regulation; Glycolysis; Histone acetylation; Keto acid dehydrogenase complex family; Krebs cycle; Metabolic diseases; Metabolon; Mitochondria; Mitochondrial pyruvate carrier; Nuclear function; Pyruvate oxidation regulation; Respirasome; Structural biology; TCA cycle

DOI:  https://doi.org/10.1007/978-3-032-26629-3_9
Biomolecules. 2026 Jun 09. pii: 842. [Epub ahead of print]16(6):

Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.

Giampaolo Morciano, Ruggiero Gorgoglione, Vito Porcelli, Amer Ahmed, Pasquale Scarcia, Angelo Vozza, Francesco Massimo Lasorsa, Giuseppe Fiermonte, Luigi Palmieri.

  Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death.

Keywords:  SLC25 carriers; metabolism; mitochondrial dynamics; neurodegeneration

DOI:  https://doi.org/10.3390/biom16060842
Biochem Biophys Res Commun. 2026 Jun 20. pii: S0006-291X(26)00947-2. [Epub ahead of print]829 154183

CIRBP maintains skeletal muscle mitochondrial energy homeostasis via mt-ATP6 to ameliorate sarcopenia.

Zhouyi Wang, Yang Guo, Zhen Hu, Hongyong Zhang, Qingmei Liu.

  Sarcopenia, characterized by progressive loss of skeletal muscle mass and function, represents a major public health challenge in aging societies; its underlying molecular mechanisms remain incompletely understood, and no approved disease-specific pharmacotherapy exists. Here, we demonstrate that CIRBP is essential for skeletal muscle homeostatic maintenance during aging. Eighteen-month-old Cirbp-/- mice exhibited a canonical sarcopenic phenotype-reduced compound muscle action potential amplitude, decreased grip strength, accelerated fatigue, and prominent myofiber atrophy-accompanied by coordinate upregulation of the ubiquitin-proteasome effectors Atrogin-1, MuRF1, and Myostatin. Whole-transcriptome RNA sequencing identified 814 differentially expressed genes, predominantly downregulated, among which mt-Atp6-encoding mitochondrial ATP synthase subunit 6-exhibited the most pronounced reduction in absolute expression. CIRBP deficiency led to coordinate downregulation of Atp6 mRNA and ATP6 protein, accompanied by severe mitochondrial cristae disruption and oxidative phosphorylation dysfunction, collectively producing chronic energy insufficiency that drove protein degradation pathway activation and progressive myofiber atrophy. Conversely, AAV-mediated CIRBP overexpression simultaneously upregulated ATP6 expression, suppressed protein degradation pathway activation, and substantially improved skeletal muscle function in aged mice at both electrophysiological and mechanical levels. This study establishes the CIRBP-Atp6 mRNA-mitochondrial energy metabolism regulatory axis as a central node in skeletal muscle aging homeostasis, providing a new mechanistic framework and potential therapeutic targets for sarcopenia intervention.

Keywords:  Cold-inducible RNA-Binding protein; Mitochondrial ATP synthase subunit 6; Mitochondrial dysfunction; Sarcopenia; Skeletal muscle aging

DOI:  https://doi.org/10.1016/j.bbrc.2026.154183
bioRxiv. 2026 Jun 10. pii: 2026.06.09.730804. [Epub ahead of print]

Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.

Michel Thiebaut de Schotten, Cynthia C Liu, Catherine Kelly, Ke Bo, Tor D Wager, Eugene V Mosharov, Martin Picard.

Mitochondria support the bioenergetic processes that enable brain function and cognition, but we have lacked a label-free, non-invasive approach to explore how brain mitochondria are linked to ageing, disease, and cognition in humans. A recently introduced MitoBrainMap neuroimaging framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here, we tested whether this framework captures meaningful age- and pathology-related mitochondrial variation. Consistent with existing literature, we find that MR-predicted mitochondrial density and tissue respiratory capacity consistently declined with age, whereas mitochondrial respiratory capacity-an index of mitochondrial quality-was relatively preserved across the lifespan. Moreover, the relations among specific mitochondrial features predicted from our algorithm were consistent with their biological organization, supporting preliminary construct validity for MR-predicted mitochondrial features. In patients with rare mitochondrial diseases, predicted maps revealed region-specific alterations in mitochondrial density and respiratory chain components, particularly the expected compensatory upregulation of complex II, but not of other mitochondrial genome-encoded components. Finally, the MR-based mitochondrial features were associated with the energetic stress marker GDF15 measured in blood, as well as with cognitive performance measures, linking the novel predictions of brain mitochondria to systemic stress and behavior. These findings introduce a first-generation, label-free, neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.

DOI: https://doi.org/10.64898/2026.06.09.730804
Metabolites. 2026 May 29. pii: 372. [Epub ahead of print]16(6):

Screening and Stratification Utility of GDF-15 and FGF-21 in Individuals Evaluated for Suspected Mitochondrial Disease: A Malaysian Cohort Study.

Affandi Omar, Dyg Pertiwi Abg Kamaludin, Wan Ahmad Syazani Mohamed, Fatimah Diana Amin Nordin, Rosnani Mohamed, Badrul Hisyam Razali, Imilia Ismail, Ngu Lock Hock, Julaina Abdul Jalil.

  Background/Objectives: Early detection of mitochondrial disorders remains challenging due to phenotypic heterogeneity and limited access to definitive molecular diagnostics. Circulating biomarkers such as growth differentiation factor-15 (GDF-15) and fibroblast growth factor-21 (FGF-21) have emerged as potential adjunct indicators. This study evaluated the screening and stratification utility of GDF-15 and FGF-21 in individuals assessed for suspected mitochondrial disease. Methods: Archived biological specimens collected between 2016 and 2017 were analysed from 221 individuals stratified into clinically high-risk, screen-positive non-high-risk, post-mortem unexplained death and healthy controls groups. Plasma and fibroblast lysate concentrations of GDF-15 and FGF-21 were quantified using enzyme-linked immunosorbent assays. Biomarker performance was assessed using receiver operating characteristic (ROC) analysis, comparative group analysis and correlation testing across clinically defined referral groups. Results: Both biomarkers were significantly elevated in clinically high-risk and screen-positive individuals compared with controls. GDF-15 demonstrated better discriminatory performance than FGF-21, with an area under the curve (AUC) of 0.7187 ± 0.0556 versus 0.6301 ± 0.0603. At a threshold of 300 pg/mL, GDF-15 demonstrated high sensitivity with moderate specificity for differentiation between clinically defined high-risk individuals and controls. Correlation analysis showed weak associations between GDF-15 and lactate and ammonia, while FGF-21 correlated modestly with glucose and alkaline phosphatase. A moderate positive correlation was observed between GDF-15 and FGF-21 across the overall cohort. Conclusions: GDF-15 and, to a lesser extent, FGF-21 may support early screening and stratification of individuals evaluated for suspected mitochondrial disease and assist in prioritising cases for further diagnostic evaluation.

Keywords:  FGF-21; GDF-15; biomarker screening; inborn errors of metabolism; mitochondrial disease

DOI:  https://doi.org/10.3390/metabo16060372