Mitochondrion最新文献

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.

Autism spectrum disorders (ASD) is a complex neurodevelopmental condition characterized by a gamut of impairments in social interaction, communication, and behaviour. Emerging evidence implicates mitochondrial dysfunction, manifested through disruptions in ATP synthesis, mitochondrial DNA (mtDNA) mutations, and heightened oxidative stress, as a significant contributor to the pathophysiology of ASD. Notably, individuals with ASD demonstrate a higher prevalence of mitochondrial disorders compared to the general population, suggesting a potential pathogenic link. However, the relationship between mitochondrial dysfunction and ASD is heterogeneous and varies among individuals, reflecting the disorder's intrinsic complexity. Recent interest in the Mitochondrial Unfolded Protein Response (UPR^mt), which is activated in response to mitochondrial stress and misfolded proteins, underscores its critical role in maintaining mitochondrial integrity. Yet, its specific implications in ASD have been insufficiently investigated. This review aims to consolidate the current literature on UPR^mt-related biomarkers in the context of ASD, elucidating how disruptions in this pathway may exacerbate mitochondrial dysfunction and contribute to ASD pathogenesis. In this narrative review, based on our literature search from academic databases such as PubMed, Scopus, Web of Science, and Google Scholar, and also grey literature, we present a conceptual framework to enhance our understanding of ASD pathophysiology that integrates mitochondrial stress, UPR^mt activation, and neurodevelopmental outcomes. This review aims to expand the existing knowledge of mitochondrial contributions to ASD and identify new research dimensions to explore the mechanisms underlying UPR^mt deregulation in ASD pathophysiology, thereby highlighting the potential therapeutic directions for targeting mitochondria-mediated UPR^mt dysfunction in ASD.

Mitochondria are morphologically and functionally heterogeneous and dynamically adapt to the current metabolic status of their hosting cell. Moreover, they are prominent sources but also sensitive targets of redox modulation and oxidative stress. Such subcellular ROS/redox signals are considered pivotal aspects in health and disease. Yet, their deciphering requires advanced optical tools. Here we took advantage of transgenic redox-indicator mice expressing a mitochondria-targeted reduction/oxidation-sensitive green fluorescent protein (roGFPm) in excitatory projection neurons. By excitation-ratiometric two-photon microscopy we quantified in acute brain slices the redox conditions of individual mitochondria. After developing adequate redox sensor calibrations and solving laser-mediated bleaching issues, we finally chose caudoputamen, which showed the most promising mitochondrial arrangement for our imaging approach. Confirming the reliability of single-mitochondria redox imaging, we characterized the interplay of redox state and mitochondrial morphology. In general, roGFPm was more oxidized in spherical than in filamentous mitochondria. Acute hypoxia reverted mitochondria to a more roundish shape and evoked a reducing shift. Furthermore, the fraction of spherical mitochondria increased with aging. Around postnatal day (pd)350, a significantly higher fraction of roundish mitochondria was present in females than in males. In addition, from pd150 on, female mice showed lower degrees of roGFPm oxidation than males. Both findings might be linked to estrogen levels, which decrease in female mice with reproductive senescence around pd350. In view of the pivotal role of mitochondria for cellular wellbeing and their involvement in various neuropathologies, the established single-organelle redox-imaging approach will foster further detailed studies.