bims-ripira 2025-12-21 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2025–12–21
six papers selected by
Martín Lopo

Amino acid supplementation in mitochondrial aminoacyl-tRNA synthetase defects: two case reports of tyrosine supplementation in YARS2-associated disease and a review of the literature.
Biomimetic siRNA therapeutics attenuate mitochondrial DNA damage and cytokine storm in sepsis.
Counseling and Prognostic Challenges in Survivorship and Mortality in Primary Mitochondrial Disease: Reshaping a Once Bleak Landscape.
Changes in plasma concentration of cell-free DNA in response to physical activity.
Comprehensive Iranian guidelines for the diagnosis and management of mitochondrial disorders: an evidence- and consensus-based approach.
Pathogen-induced mitochondrial dysfunction: mechanistic insights, immune crosstalk, and therapeutic opportunities.

Front Pediatr. 2025 ;13 1699348

Amino acid supplementation in mitochondrial aminoacyl-tRNA synthetase defects: two case reports of tyrosine supplementation in YARS2-associated disease and a review of the literature.

Giulia Ferrera, Giorgia Segre, Eleonora Lamantea, Daniele Ghezzi, Marta Rivelli, Anna Ardissone.

   Background: Mitochondrial diseases (MDs) caused by pathogenic variants in aminoacyl-tRNA synthetase (ARS) genes, either cytosolic (ARS1) or mitochondrial (ARS2), are rare and clinically diverse. YARS2 deficiency causes myopathy, lactic acidosis, and sideroblastic anemia (MLASA2). No treatments exist, although targeted amino acid (AA) supplementation could function as a possible therapy, as many ARS variants retain partial activity. While benefits have been reported in several ARS1 disorders, evidence in ARS2 diseases, including YARS2 deficiency, remains limited.
Methods: We report two siblings with genetically confirmed MLASA2 due to homozygous YARS2 variants who received oral tyrosine for 12 months. Clinical, biochemical, cardiac, and thyroid safety assessments were performed at baseline and follow-up. Standardized measures tracked motor function, symptoms, and quality of life. A systematic review of AA supplementation in ARS2 deficiencies was also conducted.
Results: Tyrosine was well tolerated. The more severely affected sibling showed improvements in motor function, endurance, and quality of life, with modest prolongation of transfusion intervals. The milder sibling reported increased energy and functional gains. Cardiac function remained stable. Literature review revealed only five prior ARS2 cases treated with AA supplementation, with variable outcomes.
Conclusion: YARS2-related MLASA2 is a severe disorder associated with high morbidity and premature mortality. No spontaneous recovery has been reported, supporting tyrosine as the likely driver of observed improvements. No cardiac or thyroid toxicities were detected during treatment. Prior reports, although limited, support the feasibility of this treatment. Our findings suggest tyrosine is a promising candidate therapy in YARS2 deficiency; larger multicenter studies are needed to validate our data.

Keywords:  ARS2; MLASA2; YARS2; amino acids; aminoacyl-tRNA synthetase defect; treatment; tyrosine

DOI:  https://doi.org/10.3389/fped.2025.1699348
J Control Release. 2025 Dec 12. pii: S0168-3659(25)01159-9. [Epub ahead of print] 114545

Biomimetic siRNA therapeutics attenuate mitochondrial DNA damage and cytokine storm in sepsis.

Sijia Jiang, Yang Zhou, Chenglong Ge, Renxiang Zhou, Mengyao Ren, Lichen Yin, Jiang Zhu.

  During the progression of severe sepsis, the oxidized mitochondrial DNA (mtDNA) in macrophages is cleaved by flap-structure-specific endonuclease 1 (FEN1) into small fragments, which are subsequently released into the cytosol and extracellular space to activate multiple pro-inflammatory signaling pathways such as NLRP3 inflammasome, cGAS-STING, and TLR9-NF-κB. Herein, biomimetic nanocomplexes (NCs) partially cloaked with macrophage membrane (MM) are developed to efficiently deliver FEN1 siRNA (siFEN1) into macrophages for sepsis management. To construct the NCs, membrane-penetrating, helical polypeptide (PG) first condenses siFEN1 and forms the cationic inner core, which is further coated with MM. By optimizing the membrane protein/siFEN1 weight ratios, partial membrane coating can be achieved, which enables the formation of NCs with both enhanced serum stability and efficient macrophage uptake efficiency. After systemic administration in cecal ligation and puncture-induced sepsis mice, the NCs exhibit prolonged blood circulation time and effective accumulation to the inflamed tissues, facilitated by MM-mediated charge neutralization of the cationic nanocore and inflammation homing. Subsequently, the NCs are efficiently internalized by macrophages through the interaction between the partially exposed polycationic core and the target cell membranes, provoking robust FEN1 silencing to suppress mtDNA fragmentation and leakage. Consequently, the NCs effectively restore immune homeostasis in sepsis mice, thereby mitigating cytokine storm and alleviating multiple organ failure.

Keywords:  Cytokine storm; Macrophage membrane coating; Mitochondrial DNA fragmentation; Sepsis; siRNA delivery

DOI:  https://doi.org/10.1016/j.jconrel.2025.114545
Pediatr Neurol. 2025 Nov 27. pii: S0887-8994(25)00370-4. [Epub ahead of print]175 223-228

Counseling and Prognostic Challenges in Survivorship and Mortality in Primary Mitochondrial Disease: Reshaping a Once Bleak Landscape.

Ibrahim Elsharkawi, Amy Goldstein, Rebecca D Ganetzky, Eva Morava.

  Primary mitochondrial diseases comprise a clinically, genetically, and biochemically heterogenous group of disorders associated with multisystemic involvement and significant morbidity and mortality of various etiologies. To date, no disease modifying therapies have been FDA approved, and treatment is largely symptomatic and supportive. Because of the rarity of mitochondrial specialists, most patients with mitochondrial diseases are cared for by clinicians without mitochondrial-specific expertise. Therefore, these clinicians by necessity rely on existing literature or older prognostic approaches which may be discordant with modern clinical practice and evolving therapeutic strategies and outcomes. Furthermore, existing literature may be skewed to the more severe end of the spectrum as publications may disproportionately focus on the most severe or unusual cases. Prognostic, therapeutic, and palliative discussions should ideally take place in a multidisciplinary setting where shared decision making can take place between the patient, family, and clinician team. Prognosis is increasingly shaped by the unprecedented development of various therapeutic modalities and personalized medicine. We aim to highlight the multipronged challenges and considerations faced in counseling patients and caregivers and draw from our own patient cohorts and observations in contemporary mitochondrial medicine to offer additional insights and future considerations for approaching patient counseling and prognostication.

Keywords:  Leigh syndrome; MELAS; Mitochondrial disease prognosis; Mitochondrial dysfunction; Primary mitochondrial disease; Survivorship

DOI:  https://doi.org/10.1016/j.pediatrneurol.2025.11.019
Arch Med Sci. 2025 ;21(5): 1703-1712

Changes in plasma concentration of cell-free DNA in response to physical activity.

Jaroslav A Hubacek, Dana Dlouhá, Hana Wünsch, Kryštof Slabý, Sabína Oreská, Aneta Prokopcová, Marian Rybář, Michal Vrablik, Michal Tomčik.

   Introduction: Plasma concentrations of cell-free DNA (cfDNA) serve as markers of overtraining or muscle injury. We examined whether nuclear (n) or mitochondrial (mt) cfDNA has potential as a marker of muscle burden or damage.
Material and methods: Ten healthy, physically active volunteers (6 females, aged 27.1 ±6.8 years) performed a downhill running test. Samples for cfnDNA and cell-free mitochondrial DNA (cfmtDNA) analysis were collected before, 30 min, 1 h, and 14 days after the downhill run. CfnDNA and cfmtDNA (two markers for each) were analyzed using qPCR.
Results: There was an extreme (~40-fold) increase in cfnDNA at the 30-min time-point against the baseline (p < 0.00001 for both markers), followed by a quick drop to baseline levels after 1 h after the end of the downhill run for all subjects. In contrast, plasma levels of cfmtDNA did not increase significantly (p = 0.27 and 0.12). It reflects the fact that in 6 subjects, the pattern was similar as for cfnDNA, but in 4 subjects a decrease of cfmtDNA concentration was observed at the 30-min time-point. These differences correlate with age, body mass index, and sex of the participants. Plasma cfnDNA significantly (p < 0.01 for all) correlated with concentrations of muscle damage markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LD), and chemokines MIP-1α and IP-10 (positive). No homogeneous correlation between cfmtDNA and biomarkers was detected.
Conclusions: Our study confirmed the extreme release and clearance of cfnDNA in physically active subjects after strenuous exercise. In contrast, the trajectory of cfmtDNA concentrations seems to have much higher inter-individual variability than cfnDNA concentrations.

Keywords:  cell-free DNA; mitochondria; nucleus; physical activity

DOI:  https://doi.org/10.5114/aoms/205792
Orphanet J Rare Dis. 2025 Dec 19. 20(1): 623

Comprehensive Iranian guidelines for the diagnosis and management of mitochondrial disorders: an evidence- and consensus-based approach.

Setila Dalili, Noushin Rostampour, Seyedeh Tahereh Mousavi, Saeid Sadeghi Joni, Nejat Mahdieh, Afagh Hassanzadeh Rad, Seyede Tahoura Hakemzadeh, Sara Nikpour, Ali Talea, Hossein Moravvej.

  Mitochondrial disorders are a heterogeneous group of inherited metabolic diseases resulting from dysfunctions in oxidative phosphorylation. These conditions predominantly affect high-energy-demand organs such as the brain, heart, liver, and muscles, leading to diverse clinical manifestations and diagnostic challenges. This article presents the first comprehensive Iranian guideline for the diagnosis and management of mitochondrial diseases, developed through an evidence-based and consensus-driven methodology. We conducted a structured literature review across major biomedical databases from 2000 to 2023 and engaged a multidisciplinary panel of Iranian experts to establish context-specific recommendations. The guideline covers clinical presentations, laboratory biomarkers, neuroimaging features, genetic diagnostics, and treatment approaches including "cocktail therapy" and acute management protocols. It also integrates a mitochondrial disease scoring system to standardize diagnosis and provides detailed insights into safe anesthesia practices for affected individuals. Special attention is given to practical implementation in resource-limited settings. These guidelines aim to enhance diagnostic accuracy, optimize management strategies, and improve the quality of life for patients with mitochondrial disorders across Iran and similar healthcare systems.

Keywords:  Diagnosis; Genetic testing; Mitochondrial diseases

DOI:  https://doi.org/10.1186/s13023-025-04127-y
Front Cell Infect Microbiol. 2025 ;15 1714998

Pathogen-induced mitochondrial dysfunction: mechanistic insights, immune crosstalk, and therapeutic opportunities.

Yang Yang, Yuanyuan Zeng, Zeyi Liu, Jian-An Huang.

  Mitochondria have emerged as multifunctional organelles central to cellular metabolism, innate immunity, and cell fate determination. Increasing evidence demonstrates that pathogens-including viruses, bacteria, fungi, and parasites-target mitochondria to modulate host immune responses and metabolic reprogramming. Disruption of mitochondrial dynamics, excessive reactive oxygen species (ROS) generation, mitochondrial DNA (mtDNA) release, and altered mitophagy represent key hallmarks of pathogen-induced mitochondrial dysfunction. These processes not only compromise cellular bioenergetics but also influence immune signaling cascades, such as cGAS-STING and NLRP3 inflammasome pathways, thereby shaping infection outcomes. This review synthesizes the latest findings on how distinct pathogen classes orchestrate mitochondrial damage and explores their implications for infection biology and immune regulation. Furthermore, we highlight emerging mitochondria-targeted therapeutic strategies and future research directions aimed at mitigating infection-induced mitochondrial pathology.

Keywords:  host defense; infection; mitochondria; mitochondrial dynamics; pathogens

DOI:  https://doi.org/10.3389/fcimb.2025.1714998