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Updated: May 9, 2026
08:56
Modeling Mitochondrial Disease Using Brain Organoids: A Focus on Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes
Published on: October 10, 2025
Inositol-related gene knockouts mimic lithium's effect on mitochondrial function.
Lilach Toker1, Yuly Bersudsky2, Inbar Plaschkes3
11] Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel [2] Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel [3] Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Summary
Lithium treatment and genetic alterations affecting inositol metabolism both upregulate mitochondrial genes in mice. This suggests mitochondrial dysfunction is linked to bipolar disorder and may be a target for lithium therapy.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- The inositol-depletion hypothesis suggests lithium affects phosphatidylinositol signaling.
- Knockout (KO) mice of inositol metabolism genes (IMPA1, Slc5a3) exhibit lithium-like phenotypes.
- Previous studies demonstrated lithium-like neurochemical and behavioral phenotypes in these KO mice.
Purpose of the Study:
- To identify pathways mediating the effects of lithium and inositol metabolism gene KO.
- To investigate the role of mitochondrial function in lithium's behavioral effects.
- To explore the link between inositol metabolism, mitochondrial dysfunction, and bipolar disorder.
Main Methods:
- DNA-microarray analysis of lithium-treated mice and IMPA1/Slc5a3 KO mice.
- Bioinformatic analysis of gene expression data using three different approaches.
- Real-time PCR validation of key mitochondrial gene expression.
- Behavioral studies using rotenone (mitochondrial inhibitor) in conjunction with lithium.
Main Results:
- Upregulation of mitochondria-related genes (Cox5a, Ndufs7, Ndufab) in the frontal cortex of lithium-treated and KO mice.
- These upregulated genes are involved in the mitochondrial electron transport chain and linked to bipolar disorder.
- Rotenone treatment counteracted lithium's behavioral effects, supporting mitochondrial involvement.
Conclusions:
- Mitochondrial dysfunction is implicated in bipolar disorder and can be ameliorated by lithium.
- Lithium may exert its behavioral effects by altering inositol metabolism and subsequently impacting mitochondrial function.
- The study provides evidence for a mechanistic link between inositol metabolism, mitochondrial pathways, and lithium's therapeutic actions.
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