Researchers from the Max Planck Institute of Immunobiology and Epigenetics, along with scientists from the Universities of Freiburg and Bonn, have unveiled the pivotal role of the histone acetyltransferase MOF in regulating mitochondrial physiology and function. Their study, published in Nature Metabolism, highlights MOF's involvement in protein acetylation, which has far-reaching implications for cellular metabolism and various diseases.
MOF, an enzyme known for acetylating histone proteins in the nucleus to regulate gene expression, has recently been found in mitochondria. However, its impact on mitochondrial function remained unclear. The team's research revealed that MOF plays a crucial role in maintaining mitochondrial integrity through the acetylation of specific mitochondrial proteins.
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In mouse studies, they identified a set of mitochondrial proteins whose acetylation status changed when MOF was lost, leading to mitochondrial defects. These defects included fragmentation, reduced cristae density, and impaired oxidative phosphorylation. Oxidative phosphorylation is vital for energy production and cell function.
One key target of MOF-mediated acetylation was COX17, a protein that plays a crucial role in mitochondrial energy production through complex IV. The researchers found that acetylation of COX17 stimulates its function, enhancing oxidative phosphorylation. Loss of acetylation impairs its function, demonstrating the significant impact of protein acetylation on mitochondrial function.
These findings challenge conventional thinking about the role of epigenetic factors and their influence on cellular function. They also have potential implications for understanding the molecular pathways behind developmental disorders and mitochondrial diseases. In experiments with patient-derived fibroblasts carrying MOF mutations, the researchers were able to partially reverse respiratory defects using acetylation-mimetic COX17 or mitochondrial MOF.