Ulcerative colitis in a child with mitochondrial disease: a case report

What does the Australian public know about mitochondrial donation and think about its potential clinical implementation? 1042 people aged ≥18 years living in Australia completed an online anonymous survey between October and December 2022. Participants were recruited through a market research company. The survey included multiple choice and Likert-scale questions gauging respondents' knowledge and attitudes. Bivariate analysis investigated differences in support for mitochondrial donation based on different sociodemographic groups. Just 19% of respondents had ever heard of mitochondrial donation prior to participation (n = 202). The average level of agreement with the statement 'If the clinical trial proves mitochondrial donation is safe, I support it becoming available in Australia' was 3.36 out of a possible 4, indicating agreement. Significant differences in the average agreement level were reported across the different 'prior use of assisted reproductive technology', 'sexual orientation', 'genetic condition' and 'mitochondrial disease' groups; however, the average level of agreement in each group was consistently >3. The findings indicate broad public support for the clinical implementation of mitochondrial donation in Australia, provided that clinical trials demonstrate its safety. Although these results may not extrapolate directly to other contexts, they may guide other jurisdictions in considering their position towards mitochondrial donation.

Detection and localization of single-nucleotide mutations in synthetic oligonucleotides by ultra-high-performance liquid chromatography coupled with high-resolution tandem mass spectrometry.

A CRISPR/dCas9 mediated electrochemical impedimetric biosensor for sensitive mtDNA detection.

LGMDR8 is a very rare autosomal recessive limb-girdle muscular dystrophy caused by variants in the TRIM32 gene. To date, 92 cases have been reported, mainly in the Hutterite population with a founder effect. This study aimed to describe a cohort of European origin and to investigate genotype-phenotype correlations. We conducted a retrospective, multicenter study of 14 French patients with genetically confirmed LGMDR8. Clinical, histological, electrodiagnostic, imaging, and genetic data were collected and compared with those from previously published cases. Patients showed a slowly progressive disease course, with a mean age at onset of 25.1 years (range 7.5-40.0). The main presenting symptom was proximal lower limb weakness (n = 13). At last follow-up, all patients had proximal lower limb weakness, 10/14 had upper limb involvement, and 10/14 had distal lower limb weakness. Six patients lost ambulation (mean disease duration: 27.3 years). No cardiac or respiratory involvement was observed. Mean creatine kinase levels were mildly elevated (4.5× upper limit of normal). Muscle biopsies exhibited dystrophic features. Ragged-red and COX-negative fibers were observed in two patients. Muscle magnetic resonance imaging revealed symmetrical involvement predominantly affecting posterior thigh muscles. Fourteen distinct pathogenic variants were identified, including eight new ones. Six variants were located in the C-terminal domain. LGMDR8 was estimated to account for 0.9% of the LGMD cases in France. No clear genotype-phenotype correlation was found. LGMDR8 is very rare in non-Hutterite patients. Age of onset is highly variable. Variants are distributed across most protein domains and did not predict clinical severity.

Mitochondrial kinase CMPK2 in immune homeostasis and disease: from metabolic regulation to inflammatory signaling.

Mitochondrial dysregulation in rheumatoid arthritis: From pathogenic mechanisms to therapeutic innovations.

The Caenorhabditis elegans mitochondrial electron transport chain: its role in adaptation, longevity, and biotechnology.

Multimodal detection of microplastics in human kidney stones and multi-omics exploration of renal cell metaflammation.

To our knowledge, only 29 individuals have been described in the literature with biallelic pathogenic variants in the valyl-tRNA synthetase 2 (VARS2) gene, responsible for changes in the mitochondrial respiratory chain complex. We report two siblings with a novel combination of biallelic variants in the VARS2 gene (c.1079C>T p.Ala360Val, likely pathogenic, and c.1258G>A p.Ala420Thr, likely pathogenic). Both presented early hypertrophic cardiomyopathy and lactic acidosis, with fatal outcomes within the first year of life. The first also presented severe fetal growth restriction and a ventricular septal defect; the second developed epilepsy, respiratory failure, and psychomotor delay. This genotype may be linked to a particularly severe cardiac phenotype. Our report broadens the clinical and genetic spectrum of VARS2-related mitochondrial disease, highlights the variability of phenotypic expression, and reinforces the importance of early molecular diagnosis in neonatal-onset cardiomyopathy. Genetic confirmation enables accurate genetic counselling and consideration of prenatal or preimplantation diagnosis in future pregnancies.

Challenging mtDNA tRNA variant guidelines: Emphasizing single-cell analysis through four novel variants.

Progressive short stature in Pearson syndrome and the impact of organ failure.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and joint destruction, driven by aberrantly activated fibroblast-like synoviocytes (RA-FLS). Mitochondrial dysfunction, particularly excessive mitochondrial fission, contributes to RA-FLS activation and apoptosis resistance, yet the impact of disease-modifying antirheumatic drugs (DMARDs) on mitochondrial dynamics remains unclear. Here, we examined the correlation between mitochondrial dynamics proteins and RA disease activity and investigated the effects of leflunomide and methotrexate (MTX) on mitochondrial dynamics, autophagy, and apoptosis in RA-FLS and collagen-induced arthritis (CIA) mice. Mitochondrial dynamics proteins in synovial fluid correlated more strongly with disease activity than those in peripheral blood, and were partially normalized in RA patients receiving leflunomide or MTX. Both leflunomide and MTX attenuated TNF-induced mitochondrial fragmentation and decreased mitochondrial membrane potential in RA-FLS. Notably, leflunomide, but not MTX inhibited DRP1 phosphorylation at Ser616, increased reactive oxygen species, and induced apoptosis via the BCL-2/BAX/caspase-3 pathway. Additionally, leflunomide influenced autophagy by promoting LC3B II/I and enhancing p62 expression. In CIA mice, leflunomide reduced the expression and phosphorylation of DRP1 on synovium, increased the expression of OPA1, and alleviated joint inflammation and destruction. These findings identify mitochondrial dynamics as a therapeutic target in RA and suggest that leflunomide promotes apoptosis of RA-FLS by modulating the mitochondrial fission-autophagy axis.

Before a spinal cord lesion in an m.3243A>G carrier is attributed to mitochondrial disease, all differential diagnoses must be excluded.

A case of a spinal cord involvement in an adult mitochondrial disease with an m.3243A>G.

Identifying the genetic cause of hereditary kidney disease is essential for appropriate management. However, pediatric patients often present with nonspecific renal symptoms such as proteinuria, hematuria, or both, making accurate diagnosis difficult. Mitochondrial diseases are also an important but underrecognized etiology of hereditary kidney disorders. This study aimed to assess the diagnostic utility of whole-exome sequencing (WES) combined with mitochondrial DNA (mtDNA) analysis and to describe the clinical and genetic features of pediatric patients presenting with isolated proteinuria, combined hematuria and proteinuria, or hematuria with a relevant family history. DNA was extracted from peripheral blood leukocytes of 77 pediatric patients with hematuria and/or proteinuria with or without family history. WES and mtDNA analyses were conducted to identify underlying genetic etiologies. The overall molecular diagnostic yield was 54.5% (42/77) with COL4A-related nephropathy (29 cases) being the most prevalent diagnosis. Notably, one patient with no systemic symptoms except for renal manifestations was identified with the m.3243A>G variant in MT-TL1, which is associated with the MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) syndrome. This patient's initial and predominant presentation was gross and microscopic hematuria, diverging from typical MELAS-associated kidney disease. WES proved valuable in diagnosing hereditary kidney diseases in pediatric patients with nonspecific urinalysis findings. Incorporating mtDNA analysis further improved diagnostic yield and enabled identification of atypical presentations of mitochondrial disorders, such as MELAS, even when renal symptoms were isolated.

Mitochondrial DNA (mtDNA) mutations are a major cause of sensorineural hearing loss (SNHL). The m.1555A >G mutation in the mitochondrial 12S rRNA gene is closely linked to nonsyndromic and aminoglycoside-induced hearing loss, leading to impaired oxidative phosphorylation (OXPHOS) and ATP production. Current treatments focus on auditory rehabilitation without addressing mitochondrial pathology. This study investigated mitochondrial transplantation as a therapeutic approach. Fibroblasts from two patients with homoplasmic m.1555A > G mutations identified during cochlear implant surgery received allogeneic mitochondria (PN-101) derived from human umbilical cord mesenchymal stem cells. Transplantation significantly increased intracellular ATP levels, complex I activity, and OXPHOS protein expression, while protecting against kanamycin-induced mitochondrial dysfunction. Importantly, PN-101 induced a heteroplasmy shift toward wild-type mtDNA, with repeated treatments sustaining and enhancing this effect. These findings demonstrate that PN-101-mediated mitochondrial transplantation improves mitochondrial bioenergetics and modulates mtDNA heteroplasmy in m.1555A > G mutant cells, suggesting a promising disease-modifying therapy for mtDNA-related hearing loss and a potential precision medicine approach.

Single-molecule mitochondrial DNA imaging reveals heteroplasmy dynamics shaped by developmental bottlenecks and selection in vivo.

Mammalian mtDNA gene expression: Concepts learned from in vivo models.

Mitochondria and Qi: Merging eastern and western medicine.