bims-curels 2026-03-22 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2026–03–22
nine papers selected by
Cure Mito Foundation

Integrated molecular and clinical profiling of primary mitochondrial oxidative phosphorylation disorders in an Indian cohort: Insights from genetics, neuroimaging, and machine learning.
m.10010T>C Mitochondrial Disease: A Case Report With Hypoparathyroidism and Review of the Literature.
Controversial issues in clinical investigation of rare disease drug development.
Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.
A meta-review of patient engagement, shared decision-making, and factors influencing equity-deserving populations' participation in clinical trials.
The role of role-playing in learning how to break bad news.
Mobile Powerhouses: Mitochondria Transfer via Tunnelling Nanotubes in Brain Health and Neurodegenerative Diseases.
MitoTracker transfers from astrocytes to neurons independently of mitochondria.
From Simulation to Conversation: Simulated Patients' Contribution to Meaningful Feedback Dialogues.

Mitochondrion. 2026 Mar 16. pii: S1567-7249(26)00040-1. [Epub ahead of print] 102150

Integrated molecular and clinical profiling of primary mitochondrial oxidative phosphorylation disorders in an Indian cohort: Insights from genetics, neuroimaging, and machine learning.

Subhadeep Banerjee, Ritwick Mondal, Shramana Deb, Gourav Shome, Sharanya Chakraborty, Chinmay Saha, Alak Pandit, Gargi Sen, Sreela Bhattacharya, Purbita Sen, Nitai P Bhattacharya, Jayanta Roy, Anjan Chowdhury, Julián Benito-León.

  Primary mitochondrial disorders are clinically and genetically heterogeneous and remain underdiagnosed in resource-limited settings. We performed a retrospective observational study (March 2016-January 2024) at a tertiary neurology center in Eastern India to characterize the clinical, biochemical, neuroimaging, electrophysiological, and molecular features of suspected mitochondrial disease and to explore interpretable machine-learning approaches for syndromic stratification. Forty-eight patients from 42 unrelated families were classified as MELAS (n = 17), chronic progressive external ophthalmoplegia (CPEO; n = 14), Leber hereditary optic neuropathy (LHON; n = 10), or Leigh syndrome (n = 7). Mean age at presentation was 23.9 years (range: 9 months-60 years), with a slight male predominance. Neuroimaging was abnormal in 23/48 (47.9%) and showed syndrome-concordant patterns, including stroke-like cortical lesions in MELAS and symmetric basal ganglia involvement in Leigh syndrome; brain MRI was typically normal in CPEO. Elevated blood and/or cerebrospinal fluid lactate was common, and electroencephalographic abnormalities were concentrated in MELAS and Leigh syndrome. Targeted molecular testing in a subset identified pathogenic mtDNA variants consistent with phenotype, including MT-TL1 variants in MELAS, m.11778G>A in MT-ND4 in LHON, and m.8993T>G in MT-ATP6 in Leigh syndrome; no mtDNA deletions were detected in tested CPEO cases. Decision tree and random forest models highlighted clinically intuitive discriminators (e.g., visual loss, external ophthalmoplegia/ptosis, and seizure phenotype), supporting their potential role as transparent triage tools for targeted molecular evaluation. This cohort provides the first detailed characterization of mitochondrial syndromes in Eastern India and supports a pragmatic diagnostic framework integrating bedside phenotyping, targeted assays, and interpretable machine learning.

Keywords:  Chronic progressive external ophthalmoplegia; Genetic diagnosis; Leber hereditary optic neuropathy; Leigh syndrome; MELAS; Machine learning; Mitochondrial disease; Neuroimaging; Oxidative phosphorylation; South Asia

DOI:  https://doi.org/10.1016/j.mito.2026.102150
Am J Med Genet A. 2026 Mar 19.

m.10010T>C Mitochondrial Disease: A Case Report With Hypoparathyroidism and Review of the Literature.

Jacob Mohr, Anja Lisbeth Frederiksen, Morten Duno, Anne Pernille Hermann, Trine Maxel Juul, Simone Rask Nielsen.

  Mitochondria are essential intracellular organelles that play a critical role in cellular metabolism, including the regulation of intracellular calcium signaling. Advances in genomic sequencing have facilitated the identification of rare pathogenic mitochondrial DNA (mtDNA) genetic variants in patients with unexplained endocrine disorders. We present a case report of a woman diagnosed with the rare mtDNA variant m.10010T>C. The case report includes a detailed clinical evaluation, heteroplasmy measurements across several tissues, and a review of previously published cases of patients heteroplasmic for the m.10010T>C variant. The patient developed myopathy and exercise-induced dyspnoea at 24 years of age. Nineteen years later, progressive muscle symptoms were accompanied by elevated blood lactate and hypoparathyroidism. Muscle biopsy revealed abnormal mitochondrial morphology with cytochrome C oxidase-negative fibers and deficiencies in respiratory chain Complexes I, II, and IV. Genetic analysis identified the m.10010T>C variant with 95% heteroplasmy in the muscle biopsy, 20% in urine, 4% in buccal mucosa, and undetectable in blood (< 1%). We report the first case of a m.10010T>C carrier with hypoparathyroidism, which is a rare and unexplained finding in mitochondrial disorders that may exacerbate myopathy.

Keywords:  hypocalcemia; hypoparathyroidism; m.10010T>C; mitochondrial disease; myopathy

DOI:  https://doi.org/10.1002/ajmg.a.70134
J Biopharm Stat. 2026 Mar 20. 1-12

Controversial issues in clinical investigation of rare disease drug development.

Shein-Chung Chow, Jiayin Zheng.

  For rare disease drug development, a single-stage hypothesis testing procedure is often considered for clinical investigation regarding safety and efficacy of a test treatment study. Under the hypothesis testing framework, "p-value less than 0.05 with at least 80% power" is often used as the gold standard in the regulatory review/approval process. This regulatory standard, however, may not be feasible in rare disease drug development due to the small patient population available and the large variability associated with the clinical outcome. To overcome this controversial issue, alternatively, it is suggested that an innovative probability-based confidence interval approach based on precision analysis be considered. The proposed probability-based confidence interval approach can not only stay away from the limitations and concerns regarding the use of p-value but also provide valuable information regarding whether the observed results are reproducible.

Keywords:  Hypotheses testing; p-value; probability monitoring procedure; probability-based confidence interval approach; regulatory flexibility; type I error rate

DOI:  https://doi.org/10.1080/10543406.2026.2644301
Nat Commun. 2026 03 16. pii: 2532. [Epub ahead of print]17(1):

Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.

Yu-Hsin Hsieh, Pauline Kautz, Lena Nitsch, Ambre M Giguelay, Janet Liebold, Veronika Dimitrova, Stephania Contreras Castillo, Freya Jungen, Gabor Zsurka, Genevieve Trombly, Markus Schuelke, Wolfram S Kunz, Caleb A Lareau, Leif S Ludwig.

Mitochondrial DNA (mtDNA) mutations occur more frequently than nuclear mutations and are associated with various diseases. While single-cell sequencing enables mtDNA variant heteroplasmy analysis, a holistic view of mtDNA mutational landscapes in individual cells has remained limited. Here, we leverage mitochondrial single-cell ATAC-seq and mtDNA-hypermutated POLGD274A knock-in HEK293 cell lines to introduce two metrics-single-cell mtDNA mutations per million base pairs (scmtMPM) and heteroplasmy-weighted mitochondrial local constraint scores (scwMSS)-to capture cellular mutational loads and somatic mosaicism. We demonstrate that individual POLGD274A cells exhibit complex mutational landscapes, with pathogenic mutations and truncating variants only present at subthreshold levels, indicative of their negative selection. In human healthy donors and mitochondriopathy patients, we identify constrained mutations in complex I, highlighting previously unrecognized mtDNA mutational landscape heterogeneity present on the single-cell level. Overall, scmtMPM and scwMSS provide a framework to investigate fundamental properties of mitochondrial genetics, disease, and somatic mosaicism.

DOI: https://doi.org/10.1038/s41467-026-70399-y
Res Involv Engagem. 2026 Mar 16.

A meta-review of patient engagement, shared decision-making, and factors influencing equity-deserving populations' participation in clinical trials.

Tamara L Morgan, Kelly Carroll, Anosha Waqar, Natasha Hudek, Meena Mosa, Dawn P Richards, Kim Meeking, Marisa Granieri, Maureen Smith, Murray Walz, Cole Etherington, Susan Marlin, Katie Gillies, Justin Presseau, Jamie C Brehaut.



Keywords:  Barriers; Community engagement; Diversity; Enablers; Equity; Equity-deserving population; Inclusion; Indigenous engagement; Patient and public involvement; Shared decision-making; Strategies; Underserved population

DOI:  https://doi.org/10.1186/s40900-026-00868-7
Tunis Med. 2025 Aug 01. 103(8): 969-974

The role of role-playing in learning how to break bad news.

Asma Mensi, Neirouz Ghannouchi, Emna Bel Haj Mabrouk, Nouha Trad, Shema Ayadi, Radhouene Debbeche.

   INTRODUCTION: Role-playing are a subtype of simulation aimed at improving non-technical skills, such as delivering a cancer diagnosis. The use of this pedagogical method in teaching bad news delivery has been growing in recent years. However, data, particularly from Tunisia, on this topic are limited.
AIM: To evaluate learners' perceptions of the usefulness of role-playing in delivering cancer diagnoses.
METHODS: We conducted a descriptive, cross-sectional study between January and October 2024. We included 4th-year medical students who had completed their gastroenterology rotations at Charles Nicolle Hospital. For each group, we conducted a role-playing session. A questionnaire was distributed to learners before and after the role-playing session to assess whether there was a change in students' opinions.
RESULTS: We collected data from 61 students. According to the students, the most crucial step for successfully delivering a diagnosis was training doctors in delivering news about serious illnesses. Nearly half of the students (n=34) reported having difficulty communicating with patients or their families. All learners were convinced that simulation plays a major role in medical practice and medical education. Additionally, all students agreed that role-playing sessions are highly suitable for teaching the delivery of bad news, particularly cancer diagnoses. Participation in role-playing sessions allows doctors to understand patients better. The learners' responses before and after the role-playing session were comparable.
CONCLUSION: Role-playing is a highly effective active learning method for teaching cancer diagnosis delivery. It helps learners approach reality more closely and acquire communication skills with patients and their families.

Keywords:  Role playing; bad news; learning

DOI:  https://doi.org/10.62438/tunismed.v103i8.5623
Eur J Neurosci. 2026 Mar;63(6): e70463

Mobile Powerhouses: Mitochondria Transfer via Tunnelling Nanotubes in Brain Health and Neurodegenerative Diseases.

Anna Henrich, Hannah Scheiblich.

  Mitochondria are central regulators of cellular metabolism, calcium homeostasis and survival. Owing to the brain's exceptional energy demand, mitochondrial dysfunction is tightly linked to neurodegenerative and neuroinflammatory disorders. Recent evidence challenges the traditional view of mitochondria as strictly cell-autonomous organelles, revealing that they can be exchanged between cells via intercellular transfer by extracellular vesicles, gap junctions or tunnelling nanotubes (TNTs) as part of an adaptive mechanism of metabolic support and signalling. Among the pathways mediating this intercellular exchange, TNTs-thin, actin-rich cytoplasmic bridges-have emerged as key conduits for mitochondrial transfer in the nervous system. TNTs enable bidirectional exchange of mitochondria between neurons, glia and vascular cells, thereby promoting bioenergetic recovery after injury and modulating immune and inflammatory responses. This review summarizes current evidence for TNT-mediated mitochondrial transfer in the brain and highlights the underlying molecular mechanisms that coordinate mitochondrial movement, including cytoskeletal dynamics, mitochondrial trafficking machinery and stress-induced signalling cascades. While mitochondrial donation can restore metabolic balance and promote neuroprotection, it may also facilitate the spread of pathological proteins, contributing to disease progression. Understanding the underlying molecular mechanism of TNT-mediated mitochondrial transfer provides a new framework for exploring metabolic communication and cellular resilience in the brain. By emphasizing emerging conceptual and mechanistic insights, we outline how advancing this field could pave the way for the development of innovative therapeutic strategies for neurodegenerative and neuroinflammatory disorders.

Keywords:  Miro1/2; actin dynamics; cell–cell connectivity; cytoskeletal remodelling; intercellular communication

DOI:  https://doi.org/10.1111/ejn.70463
Cell Rep Methods. 2026 Mar 13. pii: S2667-2375(26)00038-X. [Epub ahead of print] 101338

MitoTracker transfers from astrocytes to neurons independently of mitochondria.

Katriona L Hole, Rosalind Norkett, Emma Russell, Patrick Cottilli, Molly Strom, Jack H Howden, Nicola J Corbett, Janet Brownlees, Michael J Devine.

  The neuroprotective transfer of mitochondria from astrocytes to neurons has been primarily investigated by labeling astrocytic mitochondria with the dye MitoTracker. Here, we labeled astrocytic mitochondria with both a genetically encoded fluorophore (GFP) and MitoTracker dye and then imaged neurons immediately after co-culture with astrocytes or astrocyte-conditioned media (ACM). We report that MitoTracker transfers to neurons from both astrocytes and ACM, independently of mitochondrial transfer. Our observations provide an essential caveat to the use of this reagent and suggest that the investigation of astrocyte-neuron mitochondrial transfer, and other systems in which contact-independent transfer has been reported, requires the use of alternative labeling techniques.

Keywords:  CP: cell biology; CP: neuroscience; MitoTracker; astrocyte; intercellular mitochondrial transfer; mitochondria; neuron

DOI:  https://doi.org/10.1016/j.crmeth.2026.101338
Perspect Med Educ. 2026 ;15(1): 226-238

From Simulation to Conversation: Simulated Patients' Contribution to Meaningful Feedback Dialogues.

Annelies Lovink, Karlijn Geelkerken, Heleen Miedema, Jan-Joost Rethans, Walther van Mook, Marleen Groenier.

Introduction: Simulated patients (SPs) play a key role in medical communication training, yet their contribution to feedback dialogues during post-simulation feedback sessions remains underexplored. This study explored how SPs contribute to meaningful feedback dialogues among students during feedback sessions after simulation-based consultations.
Methods: Using an interpretivist qualitative approach, video-recorded feedback sessions with first-year technical medical students and SPs were analyzed. Episodes identified as meaningful feedback dialogues were thematically analyzed, focusing on SP contributions.
Results: Of the 120 one-minute episodes during feedback sessions, 36 episodes were classified as meaningful feedback dialogue. These were characterized by one or more of the following aspects: SPs' guidance on task performance, shifting positions of SPs, and SPs supporting the contribution of students by facilitating and creating space.
Discussion: SPs' guidance on task performance appears to respond to students' need for direction. While such guidance can support learning, it also risks reducing student reflection. Therefore, SPs need awareness of when and how to provide guidance. Although instructed to remain in the patient positions, SPs adopt multiple positions: the patient's position, the expert's position, and the meta-position during the feedback dialogue, which can enrich learning if managed consciously. Increasing SPs' awareness of these different ways of contributing to students' learning may enhance their educational impact in communication training.

DOI: https://doi.org/10.5334/pme.2247