Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Mitochondria are vital for brain function and development.
• Disruptions in mitochondrial or nuclear genomes affecting mitochondrial function lead to neurodevelopmental disorders and neurodegeneration.
• Recent advances in genome-wide technologies have accelerated the discovery of gene-disease associations in mitochondrial disorders.

Purpose of the Study:

• To review progress in functional genomics for understanding mitochondrial neurodevelopmental disorders.
• To summarize the development of small molecule therapeutics for these conditions.

Main Methods:

• Large-scale genome-wide studies in individuals with mitochondrial diseases.
• Multi-omic approaches including transcriptomics, proteomics, and metabolomics.
• Integration of deep phenotypic and genomic data, including allelic series analysis.
• Saturation genome editing for functional consequence assessment.

Main Results:

• Accelerated identification of mitochondrial disease-gene associations.
• Deeper insights into the functional impact of mitochondrial genomic variation.
• Uncovering novel mitochondrial functions and enabling gene function dissection.
• Illumination of disease mechanisms driving mitochondrial neurodevelopmental disorders.

Conclusions:

• Functional genomics and multi-omic studies are crucial for dissecting mitochondrial gene function and understanding disease mechanisms.
• Therapeutic strategies, including small molecules and RNA-DNA therapeutics, are being directed by these findings.
• This review highlights progress and future directions in treating mitochondrial neurodevelopmental disorders.