Related Experiment Video
Updated: Sep 20, 2026
Modeling Mitochondrial Disease Using Brain Organoids: A Focus on Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes
Published on: October 10, 2025
MELAS: clinical phenotype and morphological brain abnormalities
M Sparaco1, A Simonati, T Cavallaro
1UO di Neurologia con SU, Azienda Ospedaliera, Benevento, Italy.
Abstract:
We describe the clinical and neuropathological findings of three unrelated autopsy cases of MELAS harboring the A3243G transition in the mitochondrial DNA (mtDNA). Using immunohistochemical techniques, we studied the expression of several subunits of the respiratory chain in various brain regions from the same cases. In all three cases there was a reduced immunocytochemical staining for mtDNA-encoded subunits of the respiratory chain, confirming the presence of a defective mitochondrial protein synthesis in this disease. Mitochondrial abnormalities were mostly confined to multiple areas of different size and shape, in agreement with the focal character of the brain pathology in MELAS, and were most prominent in the cerebral cortex, providing a morphological contribution to the explanation of the cognitive regression of the patients. Immunoreactivity for mtDNA-encoded subunits was reduced in the walls of many pial and intracerebral arterioles of different brain regions but there was no clear correlation between territories of affected vessels and distribution of the histological and immunohistochemical lesions. Cerebral focal lesions in MELAS might have a metabolic nature and several pathogenetic mechanisms might be involved in the genesis of stroke-like episodes when there is a local increased ATP demand.
Insights
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) shows defective mitochondrial protein synthesis. This study confirms reduced respiratory chain subunit expression in brain tissue, explaining cognitive decline in MELAS patients.
Area of Science:
- Neurology
- Mitochondrial Biology
- Pathology
Background:
- Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited disorder.
- The A3243G mutation in mitochondrial DNA (mtDNA) is a common cause of MELAS.
Observation:
- Autopsy findings from three MELAS patients with the A3243G mutation were analyzed.
- Immunohistochemistry was used to examine respiratory chain subunit expression in brain tissue.
- Mitochondrial abnormalities were focal and most prominent in the cerebral cortex.
Findings:
- All cases exhibited reduced immunocytochemical staining for mtDNA-encoded respiratory chain subunits.
- This confirms defective mitochondrial protein synthesis in MELAS.
- Reduced immunoreactivity was observed in cerebral arterioles, but without clear correlation to lesion distribution.
Implications:
- The findings provide morphological evidence linking mitochondrial dysfunction to cognitive regression in MELAS.
- Focal cerebral lesions in MELAS may be metabolic in origin.
- Multiple pathogenetic mechanisms may contribute to stroke-like episodes in MELAS, potentially related to local ATP demand.
