Global variability in gene expression and alternative splicing is modulated by mitochondrial content

Area of Science:

• Molecular Biology
• Cell Biology
• Systems Biology

Background:

• Gene expression noise is a key driver of cell-to-cell phenotypic variation.
• Cellular constraints, including energy availability, are implicated in gene expression heterogeneity.
• The specific global factors governing gene expression noise remain incompletely understood.

Purpose of the Study:

• To quantify the contribution of mitochondrial variability to global gene expression noise.
• To investigate how mitochondrial content influences transcription, translation, and alternative splicing.
• To elucidate the role of cellular energy budget in phenotypic heterogeneity.

Main Methods:

• Quantification of mitochondrial variability and its correlation with gene expression noise.
• Analysis of the impact of mitochondrial content on transcription and translation rates.
• Assessment of mitochondrial influence on alternative splicing patterns using a mathematical model.

Main Results:

• Mitochondrial content variations account for approximately 50% of the observed variability in protein levels.
• Mitochondrial dosage affects the content and activity of transcription and translation machinery.
• Mitochondrial levels significantly modulate alternative splicing, impacting mRNA type and abundance.

Conclusions:

• Mitochondrial content and function are critical regulators of gene expression noise.
• Variations in mitochondrial energy production directly influence mRNA abundance, translation efficiency, and alternative splicing.
• Mitochondrial variability plays a substantial role in determining cellular phenotype through modulation of gene expression.