Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence
Mitochondrial dysfunction is a key driver of neurological disorders due to the brain’s high energy demands and reliance on mitochondrial homeostasis. Despite advances in genetic characterization, the heterogeneity of mitochondrial diseases complicates diagnosis and treatment. Mitochondrial dysfuncti...
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2025-07-01
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| author | Anna Makridou Evangelie Sintou Sofia Chatzianagnosti Iasonas Dermitzakis Sofia Gargani Maria Eleni Manthou Paschalis Theotokis |
| author_facet | Anna Makridou Evangelie Sintou Sofia Chatzianagnosti Iasonas Dermitzakis Sofia Gargani Maria Eleni Manthou Paschalis Theotokis |
| author_sort | Anna Makridou |
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| description | Mitochondrial dysfunction is a key driver of neurological disorders due to the brain’s high energy demands and reliance on mitochondrial homeostasis. Despite advances in genetic characterization, the heterogeneity of mitochondrial diseases complicates diagnosis and treatment. Mitochondrial dysfunction spans a broad clinical spectrum, from early-onset encephalopathies to adult neurodegeneration, with phenotypic and genetic variability necessitating integrated models of mitochondrial neuropathology. Mutations in nuclear or mitochondrial DNA disrupt energy production, induce oxidative stress, impair mitophagy and biogenesis, and lead to neuronal degeneration and apoptosis. This narrative review provides a structured synthesis of current knowledge by classifying mitochondrial-related neurological disorders according to disrupted biochemical pathways, in order to clarify links between genetic mutations, metabolic impairments, and clinical phenotypes. More specifically, a pathway-oriented framework was adopted that organizes disorders based on the primary mitochondrial processes affected: oxidative phosphorylation (OXPHOS), pyruvate metabolism, fatty acid β-oxidation, amino acid metabolism, phospholipid remodeling, multi-system interactions, and neurodegeneration with brain iron accumulation. Genetic, clinical and molecular data were analyzed to elucidate shared and distinct pathophysiological features. A comprehensive table synthesizes genetic causes, inheritance patterns, and neurological manifestations across disorders. This approach offers a conceptual framework that connects molecular findings to clinical practice, supporting more precise diagnostic strategies and the development of targeted therapies. Advances in whole-exome sequencing, pharmacogenomic profiling, mitochondrial gene editing, metabolic reprogramming, and replacement therapy—promise individualized therapeutic approaches, although hurdles including heteroplasmy, tissue specificity, and delivery challenges must be overcome. Ongoing molecular research is essential for translating these advances into improved patient care and quality of life. |
| format | Article |
| id | doaj-art-d60bdabd1d3b4a288c6e745d41a4cf97 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-07-01 |
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| series | Current Issues in Molecular Biology |
| spelling | doaj-art-d60bdabd1d3b4a288c6e745d41a4cf972025-08-20T03:58:26ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452025-07-0147750410.3390/cimb47070504Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic EvidenceAnna Makridou0Evangelie Sintou1Sofia Chatzianagnosti2Iasonas Dermitzakis3Sofia Gargani4Maria Eleni Manthou5Paschalis Theotokis6Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceDepartment of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceDepartment of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceDepartment of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceDepartment of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceDepartment of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceDepartment of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceMitochondrial dysfunction is a key driver of neurological disorders due to the brain’s high energy demands and reliance on mitochondrial homeostasis. Despite advances in genetic characterization, the heterogeneity of mitochondrial diseases complicates diagnosis and treatment. Mitochondrial dysfunction spans a broad clinical spectrum, from early-onset encephalopathies to adult neurodegeneration, with phenotypic and genetic variability necessitating integrated models of mitochondrial neuropathology. Mutations in nuclear or mitochondrial DNA disrupt energy production, induce oxidative stress, impair mitophagy and biogenesis, and lead to neuronal degeneration and apoptosis. This narrative review provides a structured synthesis of current knowledge by classifying mitochondrial-related neurological disorders according to disrupted biochemical pathways, in order to clarify links between genetic mutations, metabolic impairments, and clinical phenotypes. More specifically, a pathway-oriented framework was adopted that organizes disorders based on the primary mitochondrial processes affected: oxidative phosphorylation (OXPHOS), pyruvate metabolism, fatty acid β-oxidation, amino acid metabolism, phospholipid remodeling, multi-system interactions, and neurodegeneration with brain iron accumulation. Genetic, clinical and molecular data were analyzed to elucidate shared and distinct pathophysiological features. A comprehensive table synthesizes genetic causes, inheritance patterns, and neurological manifestations across disorders. This approach offers a conceptual framework that connects molecular findings to clinical practice, supporting more precise diagnostic strategies and the development of targeted therapies. Advances in whole-exome sequencing, pharmacogenomic profiling, mitochondrial gene editing, metabolic reprogramming, and replacement therapy—promise individualized therapeutic approaches, although hurdles including heteroplasmy, tissue specificity, and delivery challenges must be overcome. Ongoing molecular research is essential for translating these advances into improved patient care and quality of life.https://www.mdpi.com/1467-3045/47/7/504mitochondrial diseasesneurological manifestationsmitochondrial geneticsmetabolic pathway disruptionmitochondrial dysfunction in neurodegenerationprecision medicine |
| spellingShingle | Anna Makridou Evangelie Sintou Sofia Chatzianagnosti Iasonas Dermitzakis Sofia Gargani Maria Eleni Manthou Paschalis Theotokis Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence Current Issues in Molecular Biology mitochondrial diseases neurological manifestations mitochondrial genetics metabolic pathway disruption mitochondrial dysfunction in neurodegeneration precision medicine |
| title | Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence |
| title_full | Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence |
| title_fullStr | Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence |
| title_full_unstemmed | Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence |
| title_short | Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence |
| title_sort | mapping disorders with neurological features through mitochondrial impairment pathways insights from genetic evidence |
| topic | mitochondrial diseases neurological manifestations mitochondrial genetics metabolic pathway disruption mitochondrial dysfunction in neurodegeneration precision medicine |
| url | https://www.mdpi.com/1467-3045/47/7/504 |
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