Mitochondrial MicroRNA Regulation in Cellular Metabolism

MicroRNAs (miRNAs) localised within mitochondria—often termed mitomiRs—have emerged as pivotal regulators of energy production, redox balance and organelle dynamics. These small non-coding RNAs can derive from nuclear transcripts that are imported into mitochondria or be transcribed from mitochondrial DNA, and they act by fine-tuning the translation or stability of mitochondrial transcripts. Through modulation of oxidative phosphorylation, reactive oxygen species generation, mitochondrial fission and mitophagy, mitomiRs orchestrate adaptive responses to nutrient availability, stress and developmental cues. Dysregulation of mitochondrial miRNA networks has been implicated in cardiovascular disease, metabolic syndrome, neurodegeneration and cancer, underscoring their global significance and therapeutic potential.

Research from Nature Portfolio

Recent studies have delineated key signalling axes by which mitomiRs influence mitochondrial form and function. One foundational investigation identified an E2F1-miR-421-Pink1 pathway in cardiomyocytes: transcription factor E2F1 upregulates miR-421, which suppresses Pink1 translation and thereby promotes mitochondrial fragmentation and apoptosis under ischaemic stress. Interruption of this axis preserved mitochondrial integrity and reduced cell death in models of myocardial infarction. In a separate in vivo study of diet-induced obesity, elevated mitochondrial miR-141-3p was shown to target PTEN, impair hepatic mitochondrial respiration and elevate oxidative stress. Antagonism of miR-141-3p restored ATP generation and mitigated metabolic dysfunction, revealing a direct link between mitomiR expression, insulin resistance and non-alcoholic fatty liver disease.

Mitochondrial MicroRNA Regulation in Cellular Metabolism publication trend

The graph below shows the total number of articles in mitochondrial microrna regulation in cellular metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

microRNA (miRNA): A short non-coding RNA that binds target messenger RNAs to repress translation or promote degradation.

mitomiR: A microRNA localised within mitochondria that regulates mitochondrial gene expression and function.

Oxidative phosphorylation (OXPHOS): The series of enzyme-driven reactions in mitochondria that generate ATP through electron transport and proton gradient formation.

Mitophagy: The selective autophagic clearance of damaged or superfluous mitochondria to maintain organelle quality control.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that can signal adaptation or, in excess, cause oxidative damage.

Mitochondrial fission: The division of a mitochondrion into two organelles, a process important for quality control and distribution during cell division.

References

1. E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1. Nature Communications (2015).
2. Mitochondria-related miR-141-3p contributes to mitochondrial dysfunction in HFD-induced obesity by inhibiting PTEN. Scientific Reports (2015).
3. Mitochondrial microRNAs: New Emerging Players in Vascular Senescence and Atherosclerotic Cardiovascular Disease. International Journal of Molecular Sciences (2024).
4. Mitochondria-associated non-coding RNAs and their impact on drug resistance. Frontiers in Pharmacology (2025).