In general, mitochondrial myopathies are neuromuscular disorders caused by dysfunctional mitochondria. When mitochondria function incorrectly, ATP is not produced, and the cell suffers. With enough cells suffering, an organism can have widespread problems, resulting in systemic failures. Unfortunately, mitochondrial diseases are very promiscuous, and individual mutations in many different proteins can cause each classified disease. While many possible mutations can lead to harmful conditions for people, understanding of the proteins that cause these conditions provide insight and the ability to start creating treatments for these diseases. Therefore, discovering and evaluating the proteins behind these conditions are important for future treatments to be created.
The most common dysfunction of a mitochondria is to do with its ability to perform respiration, where oxygen is used to convert the energy stored in macronutrients into ATP, which is often necessary for effective cell growth due to the amount of ATP produced. This pathway utilizes four different enzymes, Complexes I through IV, and ATP synthase as part of the mitochondrial respiratory chain (MRC): All of which need to function properly for the pathway to work. Mutations in any complex or in the machinery used to set them up can result in a dysfunctional MRC. In fact, assembly factors are often the proteins mutated in diseased mitochondria, because without the factor to set up the complex, the enzyme fails to mature and results in a respiration defect. Therefore, assembly factors are of special concern for study of mitochondrial diseases.
A recent publication shows the evaluation of a proposed cytochrome c oxidase (CIV) assembly factor called Coa6. Discovered as a human ortholog of a yeast mitochondrial gene, its likeness to other CIV assembly factors with its mitochondrial localization and quadruple cysteine motif made it a candidate assembly factor for CIV. To uncover how Coa6 functions in the cell, they made a yeast knockout of COA6, a zebrafish knockdown of COA6, and a human cell knockdown of COA6. In yeast, the loss of the protein or loss of cysteine residues in the motif was shown to cause a respiration defect, with the levels of other CIV assembly factor proteins and CIV containing supercomplexes markedly decreasing. The human cell line seemed to support the same conclusions as the yeast strain: Coa6 is required for respiration and CIV assembly. Given that loss of the potential metal binding motif residues caused the protein to not function, Cu ions were added and rescued the respiration defect. This indicated that Coa6 was involved in copper delivery, but it was determined that Coa6 is unlikely to interact or deliver to another Cu-binding protein Sod1 (However, I disagree with this assumption, as Sod1 could have multiple copper delivery proteins or Coa6 could function as a regulator for the protein). All of these results pointed to the fact that the loss of Coa6 could lead to a mitochondrial myopathy, which was confirmed by the zebrafish system, where 72 hr and 96 hr embryos saw significant cardiac developmental defects, therefore indicating that Coa6 could be particularly essential for cardiac function.
Knowing the protein behind the condition now offers an understanding to the disease. Given that it was shown that exogenous copper could save the respiration defect, copper could be seen as a possible treatment for people with a mutation or loss of Coa6. This study gives hope that other mitochondrial disease-causing proteins can be flushed out as well, to provide a cure to these life-altering diseases.