Mitochondria, energy producing parts of cells, make their own protein factories

Mitochondria contain the tiny power plants that churn out life-sustaining energy molecules in our cells.

In 2016, the lab of Harvard Medical School geneticist Stirling Churchman showed that in yeast, cell nuclei and mitochondria synchronize their gene activity to build these power plants.

Now, the lab has revealed further details in human cells — uncovering unexpected swings in each organelle’s protein production processes that ultimately balance out for healthy cell function.

“It’s wild that the rates are so different and they still end up at the same point,” said first author Erik McShane, EMBO postdoctoral fellow in the Churchman lab.

In a recent breakthrough, scientists have delved deeper into the intricate mechanisms governing cellular energy production, shedding light on how genes housed in both the nucleus and mitochondria collaborate to generate vital ATP molecules.

Mitochondria, often dubbed the cellular powerhouses, play a pivotal role in ATP synthesis, the primary energy currency of cells. This process, known as oxidative phosphorylation (OXPHOS), relies on specialized protein complexes encoded by genes residing in both the nuclear and mitochondrial DNA.

However, the coordination between nuclear and mitochondrial gene expression for balanced OXPHOS subunit production has remained a puzzle. Researchers sought to unravel this mystery through a comprehensive analysis of the life cycles of messenger RNAs (mRNAs) in both cellular compartments.

The study revealed striking differences in the kinetics of gene expression between the nucleus and mitochondria. Mitochondrial mRNAs were found to be produced at a rate 1,100 times higher than their nuclear counterparts, yet they faced degradation seven times faster, resulting in a staggering 160-fold accumulation of mitochondrial proteins.

By meticulously examining the various stages of mRNA processing, including production, processing, ribosome association, and degradation, researchers pinpointed crucial factors governing this disparity. They identified mitochondrial factors LRPPRC and FASTKD5 as critical regulators of the process.

Further analysis led to the proposition that the highly polycistronic nature of human mitochondrial pre-mRNA is central to these differences. The researchers suggest that a 100-fold slower mitochondrial translation rate could be necessary to reconcile these disparities, highlighting the mitoribosome as a focal point of mitonuclear co-regulation.

In plain terms, this research underscores the complexity of how genes in the nucleus and mitochondria collaborate to produce cellular energy. Understanding these intricacies could hold significant implications for developing treatments for diseases linked to impaired energy production in cells.

This groundbreaking study not only advances our fundamental understanding of cellular biology but also paves the way for future investigations aimed at unraveling the mysteries of mitochondrial function and its role in health and disease.

The work deepens understanding of how mitochondrial and nuclear gene activity coordinate in healthy cells and how imbalances can lead to mitochondrial dysfunction, cellular aging, and diseases of energy metabolism, including neurodegeneration.

Such knowledge provides a foundation for researchers to one day develop ways to prevent or treat such conditions.

Findings were published in Molecular Cell.