Inside of cells, organelles carry out various functions; the mitochondria is one cellular organelle that is thought of as the powerhouse. It's a unique organelle; it carries its own DNA and has the machinery to make its own proteins. That also means that mutations in mitochondrial DNA can cause a particular subset of human disease. Researchers at the University of Helsinki have now learned more about those disorders, and have identified a potential treatment.
Humans inherit mitochondrial DNA from their mother, and this tiny genome only carries the code for making thirteen proteins, which are involved in energy metabolism. Mitochondrial disorders arise from mutations in those genes, which are widely varied in clinical presentation. The impact of the disease on patients shows that there is probably more to mitochondrial diseases than just problems with energy, however. The vast spectrum of the disorders has also made treating them difficult.
"The ability to treat patients has been stymied because of the fragmented understanding of the molecular pathogenesis and thus, bridging this knowledge gap is critical," explained Research Director Brendan Battersby of the Insitute of Biotechnology, University of Helsinki.
When proteins are produced, it's important that they have the right structure so they will function correctly. Aberrant proteins can cause problems for cells, and they have to be regulated. A gene called AFG3L2 controls the quality of mitochondrial proteins; it can help stop misfolded proteins, which are toxic, from building up. That keeps the mitochondria and cell healthy. When either the AFG3L2 or paraplegin genes carry mutations, the shape and function of mitochondria are altered.
Now, researchers in the lab of Brendan Battersby at the Institute of Biotechnology, University of Helsinki, have now learned how these genetic mutations can lead to a complex syndrome.
The scientists found that as mitochondrial proteins are newly synthesized, if the quality control over them is disrupted and aberrant proteins accumulate, a proteotoxicity triggers a cascade of downstream stress events in the mitochondria. Those events ultimately lead to a remodeling of the structure of mitochondria and a change in their function.
Interestingly, the researchers found that a drug already approved for use in the clinic and which can cross the blood-brain barrier is able to stop the production of toxic proteins, and thus reduce the resulting stress response.
"Since the mitochondrial proteotoxicity lays at the epicenter of the molecular pathogenesis, preventing the production of toxic mitochondrial proteins opens up a promising treatment paradigm to pursue for patients," said Battersby.
Next, the research team wants to follow up on this work and potentially move their efforts closer to patients by testing the drug in a mouse model.
Learn about mitochondria from the video.