bims-ripira 2026-06-21 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2026–06–21
twenty-two papers selected by
Martín Lopo

Efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency.
From Pharmacodynamic Biomarker to Evaluating Treatment Response: Biomarkers in Primary Mitochondrial Diseases.
Nao-xin-tong capsule attenuates cerebral ischemia/reperfusion injury by modulating the p53/GDF15/NOX4 regulatory network and alleviating mitochondrial dysfunction and ferroptosis-related injury.
RNF10 attenuates age-related muscle atrophy by promoting p53 degradation and alleviating oxidative stress.
Effects of β‑hydroxybutyrate on restoring autophagic flux and mitochondrial function in macrophages exposed to oxidized low‑density lipoprotein.
BCKDK protects against obesity-induced cardiac remodelling and dysfunction by alleviating mitochondrial oxidative stress and ROS-driven MAPK signalling.
High-dose accelerated intermittent theta burst stimulation targeting the primary motor cortex for gait and cognitive functions in cerebral small vessel disease: a randomized controlled trial.
Potential role of L-citrulline in regulating exercise performance and muscle protein metabolism.
Mitochondrial remodeling in obesity: mechanistic links to impaired energy metabolism and therapeutic perspectives.
Activation of AMPK as a therapeutic strategy for FBXL4-related mitochondrial DNA depletion syndrome.
Targeting Mitochondrial Dysfunction With Elamipretide (SS-31) Improves Skeletal Muscle Performance in a HFpEF Rat Model.
Association of a Homozygous TYMP c.131G>C Variant With MNGIE in a Chinese Pedigree: Insights From Genetic Analysis and Computational Modeling.
Impact of different exercise modalities on mitophagy in human skeletal muscle.
Mitochondrial cardiomyopathy: bridging molecular mechanisms and clinical frontiers.
From autophagy to mitophagy: Quality control mechanisms in skeletal muscle.
Mitochondrial protein OPA3 sustains cardiac function by regulating calcium handling in male mice.
Disease burden of untreated thymidine kinase 2 deficiency: insights from a large patient dataset.
Correction: Cell-free mitochondrial DNA as a potential predictor for hypoxic stress.
Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders.
Growth differentiation factor 11 (GDF11) signaling in neural stem cell regulation: molecular and cellular insights.
[Advances in the molecular genetics of nuclear gene mutations causing pediatric mitochondrial cardiomyopathy].
Branched-chain amino acid supplementation as a potential trigger for migraine without aura: a case report.

Brain Commun. 2026 ;8(3): fcag201

Efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency.

Michio Hirano, Caterina Garone, Richard Haas, Carmen Paradas, Fernando Scaglia, Irene Rebollo Mesa, Carl Chiang, Anny-Odile Colson, Susan VanMeter, Cristina Domínguez-González.

  Thymidine kinase 2 deficiency (TK2d) (MIM 609560) is an ultra-rare, autosomal recessive mitochondrial myopathy caused by TK2 variants, leading to mitochondrial DNA depletion and/or multiple deletions. People with thymidine kinase 2 deficiency experience progressive myopathy, bulbar weakness and respiratory insufficiency, often losing the ability to walk, eat and breathe independently. Doxecitine and doxribtimine represents the first approved treatment for patients with thymidine kinase 2 deficiency with age of symptom onset ≤12 years by the US Food and Drug Administration and the European Medicines Agency; previously, disease management was limited to supportive care. We investigated the efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency. Patients treated with pyrimidine nucleos(t)ides were pooled from retrospective (NCT03701568, NCT05017818) and prospective (NCT03845712) studies and company-supported Expanded Access Programs. Untreated patients were pooled from literature reviews and a retrospective chart review study (NCT05017818). Patient subgroups were stratified by age of thymidine kinase 2 deficiency symptom onset (≤12 years and >12 years). The primary outcome was survival in 50th-percentile matched pairs of treated and untreated patients. Other outcomes included status of developmental motor milestones, ventilatory and feeding tube support, and safety. In total, 218 patients were included (treated: 104; untreated: 114). Baseline demographics and characteristics were comparable between subgroups. Most patients had an age of symptom onset ≤12 years [treated: 82/104 (78.8%); untreated: 93/114 (81.6%)]. In the age-of-symptom-onset-≤12-years subgroup, restricted mean survival time (95% confidence interval) was 29.2 (28.2, 30.3) years over the 30 years after symptom onset for treated patients and 14.4 (11.1, 17.6) years for untreated patients. Loss of ≥1 acquired motor milestone was more frequent before treatment start than after. Substantially more patients regained ≥1 lost motor milestone after treatment start than before. Ventilatory and feeding support were used across all age-of-symptom-onset subgroups, but some patients reduced or discontinued support after starting treatment and fewer patients initiated support after treatment start than before. Most treatment-emergent adverse events (TEAEs) did not lead to discontinuation. The most frequent TEAE was diarrhoea [43/50 patients (86.0%)], which was generally mild or moderate and resolved with dose reduction. Serious TEAEs occurred in 28/50 patients (56.0%); few were considered to be drug related [4/50 (8.0%)]. In total, 3/67 patients (4.5%) experienced a fatal serious TEAE, which were not considered to be drug related. These findings indicate that pyrimidine nucleos(t)ide therapy improves survival and functional outcomes in people with thymidine kinase 2 deficiency, especially those with age of symptom onset ≤12 years, and has an acceptable safety profile.

Keywords:  mitochondrial myopathy; pyrimidine nucleos(t)ide therapy; survival; thymidine kinase 2 deficiency; treatment efficacy

DOI:  https://doi.org/10.1093/braincomms/fcag201
Clin Transl Sci. 2026 Jun;19(6): e70634

From Pharmacodynamic Biomarker to Evaluating Treatment Response: Biomarkers in Primary Mitochondrial Diseases.

Sydney Stern, Karryn Crisamore, John Patton, Robert Schuck, Michael Pacanowski.

Primary mitochondrial diseases (PMDs) result from genetic variants in nuclear DNA and mitochondrial DNA which commonly lead to aberrant oxidative phosphorylation. The clinical complexity, often attributed to the underlying genetics, includes several distinct syndromes (e.g., Barth syndrome; Pearson syndrome; Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), some with overlapping symptoms. PMDs are highly heterogenous and affect multiple organs and tissues, prominently those with high energy demand such as muscle and neurologic tissues. Disease-modifying therapies for PMDs approved by the United States Food and Drug Administration are few and disease-specific, and treatment remains largely supportive in nature. The lack of robust biomarkers contributes to challenges associated with quantifying treatment responses in drug development. Recognizing this area of critical need, we sought to understand the landscape of molecular biomarkers that may inform treatment response, support clinical trials, and may be useful for regulatory decision-making. In this review, we assess the extent of evidence and challenges for each biomarker. We propose considerations for future biomarker development to measure treatment response and facilitate early drug development in PMDs by guiding dose selection and trial enrichment.

DOI: https://doi.org/10.1111/cts.70634
J Ethnopharmacol. 2026 Jun 18. pii: S0378-8741(26)00914-1. [Epub ahead of print] 122060

Nao-xin-tong capsule attenuates cerebral ischemia/reperfusion injury by modulating the p53/GDF15/NOX4 regulatory network and alleviating mitochondrial dysfunction and ferroptosis-related injury.

Jiakang Jiao, Jinfeng Shang, Mingxue Yan, Bohong Wang, Wanting Wei, Yiran Cui, Jianjun Zhang, Xin Liu.

   ETHNOPHARMACOLOGICAL RELEVANCE: Nao-xin-tong (NXT) is a representative traditional Chinese medicine prescription for replenishing qi and activating blood circulation, and has been widely used in the prevention and treatment of cardio-cerebrovascular diseases. However, the mechanisms underlying its protective effects against cerebral ischemia/reperfusion injury (CIRI) remain incompletely understood.
AIM OF THE STUDY: This study aimed to investigate whether NXT alleviates CIRI by regulating the p53/GDF15/NOX4 regulatory network, thereby improving mitochondrial dysfunction and inhibiting neuronal ferroptosis. In particular, the protective effect of growth differentiation factor 15 (GDF15) and its interaction with NXT were explored in both in vitro and in vivo models.
MATERIALS AND METHODS: An oxygen-glucose deprivation/reoxygenation (OGD/R) model in PC12 cells and a transient middle cerebral artery occlusion (tMCAO) model in rats were established. The pharmacological effects and mechanisms of NXT were evaluated using CCK-8 assay, transmission electron microscopy, biochemical assays, RT-qPCR, Western blotting, immunofluorescence, and transcriptomic analysis. In addition, recombinant human GDF15 (rhGDF15), and GDF15 knockdown were used for mechanistic validation.
RESULTS: UPLC-Q-TOF/MS identified multiple constituents in NXT. Both OGD/R and tMCAO induced marked oxidative stress, mitochondrial injury, and ferroptosis-related alterations. NXT increased cell viability, improved neuronal and mitochondrial ultrastructure, reduced ROS, MDA, and total iron levels, enhanced SOD, GSH-Px, and ATPase activities, upregulated mitochondrial electron transport chain-related targets, and reversed the abnormal expression of ferroptosis-related molecules, including GPX4 and ACSL4. Medium-dose NXT showed the most consistent protection. Mechanistically, NXT inhibited p53 nuclear translocation and downregulated p53, GDF15, and NOX4 expression. rhGDF15 further enhanced the neuroprotective effect, whereas GDF15 knockdown attenuated the therapeutic efficacy of NXT.
CONCLUSION: NXT exerts significant protective effects against CIRI by regulating the p53/GDF15/NOX4 regulatory network, reducing oxidative stress, preserving mitochondrial function, and inhibiting neuronal ferroptosis. GDF15 acts as an important endogenous protective factor and may serve as a potential therapeutic target for ischemic stroke.

Keywords:  Nao-xin-tong; cerebral ischemia reperfusion injury; ferroptosis; mitochondrial dysfunction; p53/GDF15/NOX4 regulatory network

DOI:  https://doi.org/10.1016/j.jep.2026.122060
Free Radic Biol Med. 2026 Jun 17. pii: S0891-5849(26)00887-7. [Epub ahead of print]254 168-180

RNF10 attenuates age-related muscle atrophy by promoting p53 degradation and alleviating oxidative stress.

Hong Yang, Yingxiao Zhang, Li Zhang, Xin Dai, Jing Yu, Yuxing Zhao, Donglin Fu, Yue Shu, Min Zhou, Pan Cheng, Yongxin Wu, Ying Xiang, Hailin Yang, Qian Xiao.

  Evidence identifies proteostasis imbalance and oxidative stress serve as fundamental pathological hallmarks of muscular atrophy, yet ring finger protein 10 (RNF10), a novel E3 ubiquitin ligase, in age-related muscular atrophy remains poorly characterized. Employing a natural aging mouse model and D-galactose-induced senescent C2C12 myotubes, we performed loss- and gain-of-function approaches for RNF10 with the aim of elucidating its downstream regulatory mechanisms. Aged mice showed significant declines in skeletal muscle mass and exercise capacity. Histological analysis revealed a significant reduction in gastrocnemius muscle (GAS) fiber cross-sectional area (CSA). Both in vivo and in vitro experiments showed elevated aging markers, increased inflammatory factors, decreased protein synthesis, enhanced proteolysis, and upregulated muscle atrophy indicators accompanied by nearly 50% reduction of RNF10 expression. AAV-mediated restoration of RNF10 in aged mice improved skeletal muscle mass and function, while reducing inflammatory levels and enhancing systemic antioxidant capacity. Mechanistically, RNF10 directly interacted with p53 to promote its ubiquitin-dependent degradation, which in turn reduced oxidative stress and improved mitochondrial function. In senescent myotubes, RNF10 deficiency elevated mitochondrial oxidative stress and disrupted proteostasis, effects that were rescued by p53 inhibition. TIGAR expression increased upon p53 degradation, and TIGAR silencing abolished the protective effects against myotube atrophy and oxidative stress, indicating that TIGAR is required for these beneficial outcomes. Our findings demonstrate that promoting RNF10-mediated p53 degradation represents a promising therapeutic strategy for sarcopenia intervention.

Keywords:  Muscle atrophy; Oxidative stress; Proteostasis; RNF10; Sarcopenia

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.032
Mol Med Rep. 2026 Aug;pii: 233. [Epub ahead of print]34(2):

Effects of β‑hydroxybutyrate on restoring autophagic flux and mitochondrial function in macrophages exposed to oxidized low‑density lipoprotein.

Weiguang Luo, Mei He, Huiling Wang.

  Atherosclerosis represents a major risk factor contributing to the development and advancement of cardiovascular diseases. The present study aimed to investigate the role of impaired autophagy and mitochondrial dysfunction in THP‑1 macrophages induced by oxidized low‑density lipoprotein (ox‑LDL), a key factor in atherosclerosis and cardiovascular disease. The molecular mechanism underlying the contribution of ox‑LDL to macrophage dysfunction is poorly understood. The present study aimed to determine whether β‑hydroxybutyrate (BHB) protects autophagic and mitochondrial function in THP‑1 macrophages exposed to ox‑LDL. Using cell culture, western blotting, autophagy detection assay and measurement of mitochondrial membrane potential, the present study evaluated the effect of BHB on autophagic flux and mitochondrial integrity. Ox‑LDL treatment markedly increased p62 protein levels and decreased LC3‑II/LC3‑I ratios, indicating impaired autophagy. BHB decreased p62 levels, increased LC3‑II/LC3‑I ratios and restored autophagic flux (shown by increased autophagosome numbers) and improved mitochondrial membrane potential. In addition, BHB downregulated STAT4, which was upregulated by ox‑LDL, suggesting a signaling pathway through which BHB exerts its protective effect. The present findings demonstrate that BHB enhances autophagic activity and mitochondrial function in THP‑1 macrophages under ox‑LDL stress, highlighting its potential as a novel therapeutic agent for metabolic and cardiovascular disease. Future studies should examine in vivo applications and the broader implications of BHB in atherosclerosis.

Keywords:  THP‑1 cell; autophagic flux; mitochondrial function; oxidized low‑density lipoprotein; β‑hydroxybutyrate

DOI:  https://doi.org/10.3892/mmr.2026.13943
Redox Biol. 2026 Jun 17. pii: S2213-2317(26)00264-8. [Epub ahead of print]95 104265

BCKDK protects against obesity-induced cardiac remodelling and dysfunction by alleviating mitochondrial oxidative stress and ROS-driven MAPK signalling.

Yu Liu, Ming Ma, Yan Guo, Huan Wang, Yufan Xiao, Yang Xu, Zhensheng Cai, Qianqian Wang, Wenfeng Zhou, Yujia Xiao, Kai Atlass, Hailong Cao, Yuyu Yao, Zilin Sun, Yi Fan.

   AIMS: Impaired branched-chain amino acid (BCAA) catabolism has been implicated in obesity cardiomyopathy (OCM), and systemic inhibition of branched-chain ketoacid dehydrogenase kinase (BCKDK), a key negative regulator of BCAA oxidation, improves cardiac function. However, whether cardiomyocyte-specific manipulation of BCAA catabolism is sufficient to confer cardioprotection remains unknown.
METHODS AND RESULTS: Cardiomyocyte-specific BCKDK knockout and overexpression mouse models were generated and subjected to high-fat diet feeding, followed by echocardiography, transcriptomic, metabolomic, and molecular analyses. The mechanistic findings were further validated using in vitro experiments. Despite reduced myocardial BCAA levels, cardiomyocyte-specific BCKDK deletion unexpectedly exacerbated cardiac dysfunction and ventricular remodelling in OCM. Consistently, cardiac BCKDK expression was reduced in OCM. In contrast, cardiomyocyte-specific BCKDK overexpression improved cardiac function and remodelling, accompanied by a further reduction in myocardial BCAA levels, attenuation of mitochondrial oxidative stress, and suppression of MAPK-driven inflammatory signalling. Mechanistically, BCKDK reprogrammed mitochondrial metabolism to restrain oxidative stress. Moreover, mitochondrial ROS scavenging with MitoTEMPO alleviated mitochondrial dysfunction, and reversed the MAPK activation induced by BCKDK deficiency in vitro.
CONCLUSION: These findings reveal an unexpected BCAA-independent role of BCKDK in preserving cardiomyocyte mitochondrial function and restraining inflammatory signalling in OCM. Our study identifies cardiomyocyte-intrinsic BCKDK as a potential therapeutic target, while cautioning against overestimating the cardioprotective effects of systemic BCKDK inhibition, which may be driven primarily by extracardiac mechanisms.

Keywords:  BCAA; BCKDK; Mitochondrial dysfunction; Obesity cardiomyopathy; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2026.104265
Front Neurol. 2026 ;17 1840684

High-dose accelerated intermittent theta burst stimulation targeting the primary motor cortex for gait and cognitive functions in cerebral small vessel disease: a randomized controlled trial.

Xiao-Ying Zhao, Jia-Jing Tian, Bei-Yan Guan, Hua-Wei Chen, Shi-Yao Wang, Xin-Yang Zhang, Yan-Wei Miao, Chun-Li Song, Bing-Wei Zhang.

   Background: Gait disorder and cognitive dysfunction are the most common symptoms in patients with cerebral small vessel disease (CSVD), significantly impacting patients' quality of life. Currently, there remains a lack of effective treatment for gait disorder and cognitive dysfunction of CSVD. In this randomized, single-blind, sham-controlled study, we conducted high-dose accelerated intermittent theta burst stimulation (aiTBS) in 36 patients with CSVD to investigate the efficacy and safety of high-dose aiTBS targeting the primary motor cortex (M1 area) for treating various symptoms of CSVD, particularly gait and cognitive function.
Methods: The patients were randomly assigned to two groups of real (n = 19) or sham (n = 17) aiTBS targeting the primary motor cortex. Both groups received 14 consecutive sessions of real-aiTBS or sham-aiTBS. Primary outcome was the change of 3-meter Timed Up and Go (3mTUG) duration, assessed at baseline (T0) and immediately post-intervention (T1), with follow-up evaluations at 4 weeks after intervention (T2). Secondary outcomes included changes in the Tinetti Performance-Oriented Mobility Assessment (Tinetti) score, the Chinese version of the Mini-Mental State Examination (CMMS) score, the Montreal Cognitive Assessment (MoCA) score, three-dimensional gait analysis, and multidimensional function scale scores after intervention.
Results: Compared to the sham-aiTBS group, the real-aiTBS group exhibited significantly greater improvements in multidimensional gait, cognitive, affective and autonomic nervous function assessments. At the 4-week follow-up, time effects were statistically significant for the 3mTUG duration, Tinetti, CMMS, and MoCA scores. The real-aiTBS group exhibited more pronounced group-by-time interaction effects for the 3mTUG duration, Tinetti, and CMMS scores, while no statistically significant differences from the sham-aiTBS group were observed for the MoCA score. The aiTBS intervention response is correlated to the CSVD neuroimaging features, including periventricular white matter hyperintensity, enlarged perivascular space, cortical atrophy, lacune and total CSVD burden score.
Conclusion: The aiTBS holds promise as a valuable therapeutic approach for CSVD. High-dose aiTBS targeting the M1 area improved clinical symptoms such as gait and cognitive disorder in patients with CSVD. The therapeutic response to aiTBS in CSVD patients is related to the CSVD neuroimaging phenotypes.

Keywords:  accelerated intermittent theta burst stimulation; cerebral small vessel disease; cognitive dysfunction; gait disorder; neuroimaging phenotype; primary motor cortex

DOI:  https://doi.org/10.3389/fneur.2026.1840684
NPJ Sci Food. 2026 Jun 18.

Potential role of L-citrulline in regulating exercise performance and muscle protein metabolism.

Xiaokang Lv, Yating Song, Tian Guo, Jinling Hua.

L-citrulline (L-Cit) has emerged as a potential supplement to enhance muscle performance and protein metabolism. This review summarizes evidence from rodent and human studies, highlighting its effects on muscle function, protein synthesis, and underlying mechanisms. Key areas for future research include supplementation strategies, transport and metabolism pathways, mitochondrial function, and the interaction between L-Cit, gut microbiota, and muscle health, offering insights for nutritional interventions targeting aging and sarcopenia.

DOI: https://doi.org/10.1038/s41538-026-00943-z
Physiol Behav. 2026 Jun 18. pii: S0031-9384(26)00211-8. [Epub ahead of print] 115427

Mitochondrial remodeling in obesity: mechanistic links to impaired energy metabolism and therapeutic perspectives.

Welington Henrique Justo Neto, Camila de Oliveira Ramos, Claudio Teodoro De Souza.

  Obesity is characterized not only by excessive adiposity but also by profound disturbances in cellular and systemic energy homeostasis. Metabolic inflexibility, defined as the impaired ability to adapt substrate utilization in response to nutrient availability and energetic demands, has emerged as a central feature of obesity-associated metabolic dysfunction. Increasing evidence suggests that mitochondrial remodeling represents an important mechanism linking obesity to tissue-specific metabolic alterations, systemic metabolic dysfunction, and insulin resistance. Across adipose tissue, skeletal muscle, and liver, obesity induces tissue-specific alterations in mitochondrial biogenesis, dynamics, oxidative metabolism, quality-control pathways, and redox signaling, ultimately disrupting substrate utilization and insulin signaling. Importantly, mitochondrial adaptations appear highly dynamic and context dependent, suggesting that certain responses may initially arise as compensatory mechanisms before becoming maladaptive during disease progression. In addition, translational differences between experimental models and humans contribute to the heterogeneity observed in obesity-associated mitochondrial phenotypes. Here, we integrate preclinical and clinical evidence to examine the molecular mechanisms underlying tissue-specific mitochondrial remodeling and its contribution to metabolic inflexibility. We further discuss how lifestyle, pharmacological, and surgical interventions modulate mitochondrial pathways involved in restoring metabolic flexibility and improving metabolic health. Collectively, this review highlights tissue-specific mitochondrial remodeling as a dynamic and context-dependent process linking obesity to metabolic inflexibility and impaired metabolic adaptability, while identifying mitochondrial plasticity as a promising therapeutic target.

Keywords:  Adipose Tissue; Energy Metabolism; Insulin Resistance; Mitochondria; Muscle, Skeletal; Obesity

DOI:  https://doi.org/10.1016/j.physbeh.2026.115427
EMBO Mol Med. 2026 Jun 17.

Activation of AMPK as a therapeutic strategy for FBXL4-related mitochondrial DNA depletion syndrome.

Aniketh Bishnu, Juan Zapata-Muñoz, Robert W Taylor, Kei Sakamoto, Ian G Ganley.

Distinct mitophagy pathways can eliminate not only damaged mitochondria but also healthy ones. In Mitochondrial DNA Depletion Syndrome 13 (MTDPS13), dysregulated BNIP3/NIX-driven mitophagy of functional mitochondria is thought to be the key pathological driver. Patient mutations in the E3 ubiquitin ligase FBXL4 impair the proteasomal degradation of the mitophagy receptors BNIP3 and NIX, causing their accumulation and excessive mitophagy. As a result, mitochondrial content and oxidative phosphorylation decline sharply across multiple tissues, leading to early mortality, with no effective treatments currently existing. Here, we build on our work showing that AMPK can inhibit mitophagy via sequestration of the ULK1 autophagy-initiating kinase ULK1 and demonstrate that it is also critically relevant for mitophagy induced by FBXL4 disruption. Using FBXL4-deficient cells, as well as fibroblasts derived from MTDPS13 patients and a chemically-induced mouse model, we show that small molecule AMPK activation inhibits BNIP3/NIX-mediated mitophagy and recovers functional mitochondrial content. This work therefore validates AMPK as a realistic target in treating MTDPS13.

DOI: https://doi.org/10.1038/s44321-026-00471-z
Circ Heart Fail. 2026 Jun 15. e014397

Targeting Mitochondrial Dysfunction With Elamipretide (SS-31) Improves Skeletal Muscle Performance in a HFpEF Rat Model.

Beatrice Vahle, Sven Weidner, André Tomalka, Antje Schauer, Antje Augstein, Anita Männel, Peggy Barthel, Janet Friedrich, Grietje Beck, Siegfried Labeit, T Scott Bowen, Tobias Siebert, Axel Linke, Volker Adams.

   BACKGROUND: Exercise intolerance, promoted by skeletal muscle- and mitochondrial dysfunction, has been identified as a therapeutic target in heart failure with preserved ejection fraction (HFpEF). In the context of mitochondrial dysfunction, altered cardiolipin integrity has been reported in the myocardium of HFpEF, suggesting Elamipretide, a cardiolipin stabilizing agent, as potential therapeutic approach. The present study investigated cardiolipin dysregulation in the skeletal muscle of HFpEF rats and analyzed the effect of Elamipretide treatment.
METHODS: Female zucker fatty spontaneously hypertensive heart failure F1 hybrid lean (n=10, control) and obese rats (n=24, HFpEF) were included. At 20 weeks of age, HFpEF rats were randomized into 2 groups receiving NaCl (n=12) or Elamipretide (n=12) for 12 weeks. Skeletal muscle tissue was collected for whole-muscle force, single-fiber mechanics, mitochondrial respiration, histology and molecular analyses.
RESULTS: HFpEF rats exhibited reduced cardiolipin levels (-6.8%, P=0.007) and maturation (shown via tafazzin expression), contractile dysfunction, titin hyperphosphorylation, fiber atrophy and increased oxidative stress markers. Elamipretide improved whole muscle (soleus: +8.2%, P=0.041, extensor digitorum longus: +10.9%, P=0.016) and single-fiber (soleus: +173.2%, P<0.001, extensor digitorum longus: +66.0%, P=ns) contractile function and titin phosphorylation (soleus: -35.4%, P<0.001, extensor digitorum longus: -40.2%, P<0.001), while preventing atrophy development (soleus: +49%, P=0.001, extensor digitorum longus: +54.8%, P<0.001). Improved mitochondrial function, presumably through cardiolipin-mediated improvements in oxidative phosphorylation, could be associated with muscle force and cardiolipin integrity.
CONCLUSIONS: Our data highlight cardiolipin stabilization as a key modulator of mitochondrial and contractile function in HFpEF, identifying Elamipretide as a promising therapeutic approach for skeletal muscle dysfunction.

Keywords:  animals; heart failure; mitochondria; obesity; stroke volume

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.126.014397
Mol Genet Genomic Med. 2026 Jun;14(6): e70253

Association of a Homozygous TYMP c.131G>C Variant With MNGIE in a Chinese Pedigree: Insights From Genetic Analysis and Computational Modeling.

Ling Li, Xiu Chen, Hua Li, Kai Guo, Ting Zhang, Mingyi Ma, Songhua Zhao.

   BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in TYMP, which disrupt thymidine metabolism. This study aimed to characterize a novel homozygous TYMP variant and provide insights into its potential structural and functional consequences through bioinformatic analyses.
METHODS: We identified a homozygous TYMP variant (c.131G>C, p.R44P) in a proband with MNGIE using whole-exome sequencing and Sanger sequencing. Computational structural analyses and molecular modeling were performed to predict the impact of the R44P substitution on thymidine phosphorylase (TP) stability, homodimerization, catalytic activity, and substrate binding.
RESULTS: The homozygous TYMP c.131G>C variant was confirmed in the proband. Computational analyses suggested that the p.R44P substitution may destabilize TP and potentially impair homodimerization. Molecular modeling further predicted altered thymidine binding and disrupted active-site geometry. These predicted perturbations are hypothesized to contribute to defective nucleotide metabolism, thymidine accumulation, and deoxynucleotide triphosphate pool imbalance, which may ultimately result in mitochondrial genomic instability manifesting as mitochondrial DNA deletions and depletion.
CONCLUSION: Our findings report the TYMP c.131G>C variant in a homozygous configuration, extending beyond a recently described compound heterozygous case. The bioinformatic predictions support the classification of this variant as likely pathogenic in MNGIE, though functional studies are warranted to validate these findings.

Keywords:   TYMP ; MNGIE; missense variant; nucleotide homeostasis; whole‐exome sequencing

DOI:  https://doi.org/10.1002/mgg3.70253
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00153-4. [Epub ahead of print]404 63-79

Impact of different exercise modalities on mitophagy in human skeletal muscle.

Cristóbal Muñoz-Medina, Alfonso Carriel-Nesvara, Javier Botella, Mauricio Castro-Sepulveda.

  Exercise induces profound mitochondrial adaptations in skeletal muscle, with different modalities uniquely influencing different branches of mitochondrial quality control (MQC). This review examines how endurance, resistance, and high-intensity interval training (HIIT) regulate mitophagy, the selective degradation of damaged mitochondria, in skeletal muscle (SkM). Research in rodents has shown that endurance exercise upregulates mitophagy primarily through the AMPK/PGC-1α signaling axis, promoting mitochondrial turnover and ensuring metabolic efficiency. In humans, high-intensity exercise increases mitophagy to a larger extent when compared to traditional endurance exercises. On the other hand, resistance exercise triggers alternative MQC mechanisms, including potential mitochondrial ejection. Collectively, these results suggest that mitophagy and MQC pathways are regulated in human SkM following exercise, but the specific molecular pathways seem to be specific to each exercise mode. Future studies should aim at disentangling the multiple mitophagy and MQC pathways in human SkM following exercise.

Keywords:  Aging; Exercise training; Metabolic health; Mitochondrial autophagy; Skeletal muscle plasticity

DOI:  https://doi.org/10.1016/bs.ircmb.2025.10.005
Nat Rev Cardiol. 2026 Jun 18.

Mitochondrial cardiomyopathy: bridging molecular mechanisms and clinical frontiers.

Atsuko Imai-Okazaki, Liming Pei, Douglas C Wallace.

Genetic cardiomyopathies caused by pathogenic variants in nuclear DNA (nDNA) that encodes contractile sarcomere proteins are among the best understood of all the cardiomyopathies. By contrast, mitochondrial cardiomyopathy is caused by a dysfunction in mitochondrial oxidative phosphorylation due to pathogenic variants in either nDNA or the maternal mitochondrial DNA (mtDNA). Unlike contractile protein defects, which generally follow predictable Mendelian inheritance patterns, mitochondrial cardiomyopathy is genetically complex as a result of the distinctive characteristics of the mitochondrial genome, which influence patterns of maternal inheritance, heteroplasmy and tissue-specific variations in mtDNA variant load. Both single-gene nDNA and mtDNA variants can impair cardiac energetics, resulting in a wide clinical spectrum ranging from severe, childhood-onset to milder, adult-onset cardiomyopathy. Furthermore, the intricate metabolic demands of the heart mean that mitochondrial dysfunction can be influenced by a broad array of genetic and environmental modifiers. A greater recognition of these complexities and the integration of genomic sequencing, novel biomarkers and functional imaging have advanced diagnostic and therapeutic approaches. Emerging treatment strategies, such as metabolic supplementation, gene therapy and genome editing, are under investigation. In this Review, we synthesize the molecular and clinical landscape of mitochondrial cardiomyopathy, highlighting the ongoing challenges and prospects of precision medicine in this rapidly evolving field.

DOI: https://doi.org/10.1038/s41569-026-01301-y
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00162-5. [Epub ahead of print]404 1-61

From autophagy to mitophagy: Quality control mechanisms in skeletal muscle.

Eduardo Antuña, Nerea Menéndez-Coto, Paula Fernández-Guisasola, Ana Coto-Montes.

  Autophagy is a process which is responsible for the maintenance of cellular homeostasis. This is achieved through the orchestration of both highly selective and non-selective degradation pathways, the purpose of which is the elimination of damaged structures. Recent findings have revealed that, in addition to its intracellular function, this organelle exhibits a remarkable "social life" and forms relationships with other cellular organelles. This has led to the discovery that mitochondrial quality is maintained not only through mitophagy, but also through extracellular mechanisms between cells. This has significantly expanded our understanding of tissue integrity. In skeletal muscle, autophagy, or autophagy, is a finely tuned process that plays a crucial role in maintaining physiological performance and adaptation. Disruption of autophagy has been linked to accelerated degeneration, metabolic dysfunction, and frailty. Although therapeutic manipulation of autophagy and mitophagy shows promise in restoring muscle health, major translational barriers persist. A more profound and nuanced exploration of autophagy flux in human muscle is imperative, underpinned by novel advanced cell biology technologies and predicated on satellite cells as the primary agents in muscle regeneration. The full therapeutic potential of autophagy could be harnessed to redefine interventions against muscle ageing and associated diseases. However, this would still require critical scrutiny of the long-term effects and systemic consequences.

Keywords:  Aging; Autophagy; Mitochondria; Quality control mechanisms; Skeletal muscle

DOI:  https://doi.org/10.1016/bs.ircmb.2025.11.006
Nat Commun. 2026 Jun 17.

Mitochondrial protein OPA3 sustains cardiac function by regulating calcium handling in male mice.

Na Geng, Taiwei Chen, Hao Li, Shan Lu, Yuehong Wang, Ling Gao, Donald M Bers, Xiyuan Lu.

Heart failure (HF) is a growing global health burden characterized by impaired cardiac contractility and progressive remodeling, driven in part by disrupted Ca2+ handling and mitochondrial dysfunction. However, the molecular mechanisms coordinating these processes remain incompletely understood. Here we showed that OPA3 was decreased in both human and murine HF. Cardiomyocyte-specific deletion of Opa3 in male mice led to the progressive dilated cardiomyopathy (DCM), accompanied by impaired myocardial function, calcium cycling and mitochondria function. Mechanistically, OPA3 forms multimers that are required for its interaction with phospholamban (PLN), thereby maintaining sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) activity and Ca2+ handling. OPA3 is localized to the mitochondrial outer membrane, and its absence impaired mitochondrial function. Cardiomyocyte-specific overexpression of Opa3 improved cardiac dysfunction in both pressure overload- and doxorubicin-induced HF models. Our data define a critical role of OPA3-PLN-SERCA2a axis that regulates both mitochondria and SR function, representing a potential therapeutic target for HF.

DOI: https://doi.org/10.1038/s41467-026-73991-4
Brain Commun. 2026 ;8(3): fcag200

Disease burden of untreated thymidine kinase 2 deficiency: insights from a large patient dataset.

Cristina Domínguez-González, Caterina Garone, Andrés Nascimento, Yuanjun Ma, Nada Boudiaf, Richard Kim, Susan VanMeter, Marcus Brunnert, Michio Hirano.

  Thymidine kinase 2 deficiency (MIM 609560) is an ultra-rare, autosomal recessive mitochondrial disease, resulting in progressive myopathy, respiratory insufficiency and increased risk of early death. Doxecitine and doxribtimine represents the first approved treatment for thymidine kinase 2 deficiency in the USA and the EU; previously, management was restricted to supportive care. The overall understanding of the natural history of thymidine kinase 2 deficiency is limited. Our study describes the baseline characteristics, survival and disease progression of untreated patients with thymidine kinase 2 deficiency as part of one of the largest international datasets to date. Data from individuals with thymidine kinase 2 deficiency identified through the review of published literature and a retrospective chart review study (NCT05017818) were pooled with pretreatment data from patients later treated with pyrimidine nucleos(t)ides (NCT03701568; NCT03845712; NCT05017818; company-supported Expanded Access Programs). Subgroups were stratified by age of thymidine kinase 2 deficiency symptom onset (≤12 years and >12 years). Key outcomes measured included survival, developmental motor milestone attainment, loss, regain and use of ventilatory and feeding support. In total, 257 patients were included in the study. Most patients [n = 199 (77.4%)] had an age of symptom onset ≤12 years, while 49 (19.1%) had an age of symptom onset >12 years; age of onset was missing for 9 (3.5%). Kaplan-Meier survival analyses estimated that the median time (95% confidence interval) from symptom onset to death was 2.6 (1.3, 6.4) years with age of symptom onset ≤12 years and 24.0 (16.0, not applicable) years with age of symptom onset >12 years. Loss of previously acquired motor milestones was observed across both subgroups, though most frequently in those with age of symptom onset ≤12 years [61/75 patients (81.3%) lost ≥1 motor milestone]. Spontaneous regain of lost motor milestones was rare [3/71 patients (4.2%), all with age of symptom onset ≤12 years]. Use of ventilatory support was observed for both subgroups [81/199 patients (40.7%) with age of symptom onset ≤12 years (missing data, n = 73); 23/49 patients (46.9%) with age of symptom onset >12 years (missing data, n = 11)]. Use of feeding tube support was also reported [28/199 patients (14.1%) with age of symptom onset ≤12 years (missing data, n = 121); 4/49 patients (8.2%) with age of symptom onset >12 years (missing data, n = 21)]. This study confirms the severe disease burden and high mortality associated with thymidine kinase 2 deficiency, underscoring the devastating impact on quality of life. This comprehensive dataset provides a valuable resource for informing clinical management and future therapeutic strategies.

Keywords:  mitochondrial myopathy; motor milestones; natural history; survival; thymidine kinase 2 deficiency

DOI:  https://doi.org/10.1093/braincomms/fcag200
Mol Biol Rep. 2026 Jun 19. pii: 969. [Epub ahead of print]53(1):

Correction: Cell-free mitochondrial DNA as a potential predictor for hypoxic stress.

Qiaoping Qu, Can Xiao, Xuemei Liu, Aixue Huang, Hui Li, Gang Xu, Ningsheng Shao, Yuechao Zhao, Bo Gao.

DOI: https://doi.org/10.1007/s11033-026-12125-x
Neurotherapeutics. 2026 Jun 15. pii: S1878-7479(26)00115-7. [Epub ahead of print]23(4): e00945

Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders.

Anthony C T Cheung, Saoussen Berrahmoune, Christelle Dassi, Heather Pekeles, Tommy Gagnon, Paula J Waters, Ralf Eberhard, Daniela Buhas, Kenneth A Myers.

  We evaluated the safety and efficacy of enteral deoxycytidine/deoxythymidine combination therapy in treatment of POLG-related disorders, genetic mitochondrial diseases characterized by progressive neurological degeneration. A single-centre open-label phase II trial was conducted. Inclusion criteria included: age 3 months to 60 years, clinical diagnosis of POLG-related disorder, and biallelic pathogenic POLG variants. Participants received deoxycytidine/deoxythymidine initially at 100 mg/kg/day (50 mg/kg deoxycytidine and 50 mg/kg deoxythymidine), titrated to 400 mg/kg/day over three weeks. The current protocol is a 60-month treatment period with primary outcomes the Newcastle Mitochondrial Disease Scale sections I-III and serum growth differentiation factor 15. Secondary outcomes include quality of life questionnaires, seizure diary, EEG, and blood and urine laboratory tests assessing end organ function. Outcomes were assessed at baseline, 1-month, 2-month, 3-month, and 6-month timepoints, then every 6 months thereafter. Twenty-five individuals (14 male, 11 female; mean age 12.3 years) started deoxycytidine/deoxythymidine. Five died during the trial and five withdrew. The most common treatment-related adverse event was diarrhea. Newcastle Mitochondrial Disease Scale sections I-III score decreased (improved) from baseline at all timepoints from 1 month to 24 months (p < 0.05). Serum growth differentiation factor 15 significantly decreased (improved) from baseline at 1-month, 2-month, and 3-month timepoints (p < 0.05). Quality of life score improved at 3-month, 12-month, and 18-month timepoints (p < 0.05). In summary, our data suggest deoxycytidine/deoxythymidine is safe and effective for POLG-related disorders; however, further study is needed to clarify the therapeutic mechanism(s) so that the treatment can be refined and optimized.

Keywords:  DNA polymerase gamma; Deoxynucleoside; Mitochondrial DNA depletion disorder; Mitochondrial disorder; POLG

DOI:  https://doi.org/10.1016/j.neurot.2026.e00945
Rev Neurosci. 2026 Jun 17.

Growth differentiation factor 11 (GDF11) signaling in neural stem cell regulation: molecular and cellular insights.

Farhad Mashayekhi, Zivar Salehi.

  Neurogenesis in adult mammalian brain persists in restricted areas, especially the subgranular zone (SGZ) of the hippocampus and the ventricular-subventricular zone (V-SVz), where neural stem cells (NSCs) occupy neurogenic niches. These NSC niches provide signals that regulate stem cell behavior. Among extrinsic modulators, Growth Differentiation Factor 11 (GDF11 or BMP11) which is a transforming growth factor-β (TGF-β) superfamily member, was shown to play key role in the NSC biology and brain aging. In this review, the most recent molecular mechanisms of GDF11 signaling in the regulation of NSC will be addressed. GDF11 plays mainly through activin type II receptors (ActRIIA/B) and ALK4/ALK5, activating classical Smad2/3 pathways that impact transcriptional networks controlling neural cell behavior. Moreover, GDF11 stimulates non-Smad signaling pathways - including ERK, p38, JNK, and PI3K/AKT - providing context-dependent integration of proliferative and anti-proliferative signals. Furthermore, GDF11 functions as a feedback regulator limiting the number of progenitor cells and organizing neurogenic timing. In the adult brain, GDF11 plays important role in neurovascular remodeling, glial inflammatory states, and extracellular matrix interactions. Despite its recognized roles, the effect of GDF11 on aging remains a subject of intense debate, characterized by conflicting reports regarding its circulating levels, tissue-specific dynamics, and dose-dependent effects. Recent evidence suggests that GDF11 acts as a context-dependent modulator, integrating systemic, vascular, and cellular cues to maintain NSC homeostasis and neurogenic potential. Therefore, elucidating the exact cellular and molecular mechanisms by which GDF11 controls NSC behavior is vital to advancing novel therapeutic strategies for neurodegenerative disorders and age-related cognitive decline.

Keywords:  GDF11; TGF-β/Smad signaling; brain aging; neural stem cells; neurogenesis; neurogenic niche

DOI:  https://doi.org/10.1515/revneuro-2026-0074
Zhongguo Dang Dai Er Ke Za Zhi. 2026 Jun 15. pii: 1008-8830(2026)06-0772-08. [Epub ahead of print]28(6): 772-779

[Advances in the molecular genetics of nuclear gene mutations causing pediatric mitochondrial cardiomyopathy].

Zi-Wei Wang, Yu-Qi Wang, Chun-Li Wang.

  Mitochondrial cardiomyopathy (MCM) is a heterogeneous group of disorders characterized by abnormal myocardial structure and/or function caused by defects in genes encoding the oxidative phosphorylation chain. This review systematically summarizes molecular genetic advances regarding nuclear gene mutations associated with pediatric MCM, focusing on mutations affecting pathways including respiratory chain complex subunits and assembly factors, coenzyme Q10 biosynthesis, mitochondrial DNA maintenance and expression, lipid metabolism, iron-sulfur cluster metabolism, apoptosis regulation, and mitochondrial dynamics. These nuclear gene mutations contribute to myocardial pathological changes by disrupting key processes such as mitochondrial energy metabolism, membrane stability, and signal transduction. The review provides a theoretical basis for precise clinical diagnosis and the exploration of potential molecular targets in pediatric MCM.

Keywords:  Child; Mitochondrial cardiomyopathy; Mutation; Nuclear gene; Oxidative phosphorylation

DOI:  https://doi.org/10.7499/j.issn.1008-8830.2510107
J Med Case Rep. 2026 Jun 18.

Branched-chain amino acid supplementation as a potential trigger for migraine without aura: a case report.

Mehmet Sinan Saricicek, Ali Taylan Saricicek.

   BACKGROUND: Migraine is a common and disabling neurological disorder with a wide range of reported triggers, including dietary factors and nutritional supplements. Branched-chain amino acids (BCAAs) are frequently consumed to enhance athletic performance; however, their potential role in triggering migraine attacks remains largely unexplored.
CASE PRESENTATION: A 28-year-old White man developed a severe unilateral pulsatile headache associated with nausea, vomiting, and photophobia 2 hours after consuming a BCAA supplement following exercise. Neuroimaging and laboratory investigations were unremarkable, and the patient fulfilled the International Classification of Headache Disorders, 3rd edition (ICHD-3), criteria for migraine without aura. Symptoms resolved with acute treatment, and no further attacks occurred following discontinuation of BCAA supplementation and implementation of preventive and lifestyle measures during 6 months of follow-up.
CONCLUSION: This case highlights BCAA supplementation as a potential trigger for migraine and discusses plausible neurobiological mechanisms relevant to migraine susceptibility. Further studies are needed to clarify this potential association.

Keywords:  Branched-chain amino acids; Case report; Dietary supplements; Headache triggers; Migraine

DOI:  https://doi.org/10.1186/s13256-026-06229-y