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Updated: Mar 15, 2026
Modeling Mitochondrial Disease Using Brain Organoids: A Focus on Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes
Published on: October 10, 2025
Distinctive distribution of brain volume reductions in MELAS and mitochondrial DNA A3243G mutation carriers: A
Koyo Tsujikawa1, Joe Senda2, Keizo Yasui3
1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Neurology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.
Objective:
The aim of this study was to investigate the clinically latent brain atrophy of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) harboring a mitochondrial DNA A3243G mutation (A3243G) and A3243G carriers without stroke-like episodes (SEs).
Methods:
We used voxel-based morphometry (VBM) with magnetic resonance imaging to investigate gray matter (GM) and white matter (WM) volume reductions in four MELAS patients and in five A3243G carriers compared to 16 healthy controls. In addition, we investigated the regions of previous SEs using conventional MRI.
Results:
All four MELAS patients showed significant GM volume reductions in the left superior parietal lobule (SPL), right precuneus, right middle temporal gyrus (MTG), and bilateral posterior lobes of the cerebellum. These areas of GM volume reduction were beyond the regions of previous SEs. As for A3243G carriers, GM volume reductions in the left SPL, right precuneus, right MTG, and bilateral posterior lobes of the cerebellum were detected in three, one, two, and five subjects, respectively. All four MELAS patients showed significant WM volume reductions in the bilateral or unilateral temporal sub-gyral regions, which were included in the regions of previous SEs. No A3243G carriers showed WM volume reductions.
Conclusion:
The distribution patterns of GM volume reductions in VBM may reflect a common vulnerability of the brains among MELAS patients and A3243G carriers.
Insights
Brain atrophy in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) patients with the A3243G mutation is detectable even without stroke-like episodes (SEs). Voxel-based morphometry reveals gray matter reductions in MELAS patients and carriers, suggesting common brain vulnerabilities.
Area of Science:
- Neurology
- Genetics
- Neuroimaging
Background:
- Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited disorder.
- The A3243G mutation in mitochondrial DNA is a common cause of MELAS.
- Brain atrophy can occur in MELAS, but its subclinical manifestations are not fully understood.
Purpose of the Study:
- To investigate subclinical brain atrophy in patients with MELAS harboring the A3243G mutation.
- To compare brain structure in MELAS patients and A3243G carriers without stroke-like episodes (SEs) to healthy controls.
Main Methods:
- Voxel-based morphometry (VBM) using magnetic resonance imaging (MRI) was employed.
- Gray matter (GM) and white matter (WM) volumes were analyzed in MELAS patients, A3243G carriers, and controls.
- Conventional MRI was used to identify regions of previous SEs.
Main Results:
- MELAS patients exhibited significant GM volume reductions in the superior parietal lobule, precuneus, middle temporal gyrus, and cerebellar posterior lobes, extending beyond SE regions.
- A3243G carriers showed varying degrees of GM volume reductions in these same areas.
- WM volume reductions were observed in MELAS patients within SE regions, but not in carriers.
Conclusions:
- VBM-detected GM volume reductions in MELAS patients and A3243G carriers suggest a shared brain vulnerability.
- These findings highlight the potential for subclinical neurodegeneration in individuals with the A3243G mutation.
