TACO1 Protein’s Role in Leigh Syndrome
Article Summary
- Miller School researchers are part of a team that has shown how problems with the mitochondrial protein TACO1 cause a form of Leigh syndrome.
- Most patients exhibit Leigh syndrome symptoms early in life, but a small group carrying TACO1 mutations develop the disease later in childhood.
- When TACO1 is mutated, ribosomes synthesize COX1 inefficiently, creating non-functioning proteins.
Researchers at the University of Miami Miller School of Medicine, McGill University and the Karolinska Institute have shown, for the first time, how problems with the mitochondrial protein TACO1 cause a form of Leigh syndrome, a rare, neurometabolic condition.
The team found TACO1 dysfunction makes it harder for mitochondrial ribosomes to effectively make the COX1 protein, disrupting cellular energy production. The study was published in the journal Nucleic Acids Research.
“Ribosomes are molecular machines that follow messenger RNA instructions to link amino acids together in a specified order to make proteins,” said Antoni Barrientos, Ph.D., professor of neurology and biochemistry and molecular biology at the Miller School and senior author on the study. “However, some amino acids, such as prolines, are oddly shaped and, when a protein has several consecutive prolines, that can clog up the machinery. TACO1 helps ensure that COX1, and potentially other proteins, are synthesized correctly. However, when it’s mutated, that loss of function can cause severe health problems.”
Late-onset Leigh Syndrome
Leigh syndrome is a deadly condition that causes progressive cognitive and movement loss. While most patients exhibit Leigh syndrome symptoms early in life, a small group carrying TACO1 mutations develop the disease later in childhood. McGill University researchers Hanna Antonicka, Ph.D., and Eric Shoubridge, Ph.D., were the first to identify this late-onset variety. Until now, no one understood the mechanisms driving it.
The disease is driven by dysfunctional mitochondria, cellular energy plants with an odd history. Eons ago, they were independent bacteria that were somehow incorporated into other microbes, setting the stage for multicellular organisms. Because they were once independent, these organelles have their own small complements of DNA, RNA, proteins and ribosomes. Mitochondria only produce 13 proteins, but each one is essential.
“Mitochondrial proteins are the building blocks for enzymes that convert the energy stored in nutrients into ATP, our cells’ energy currency,” said Dr. Barrientos. “If protein synthesis is compromised, it can cause mitochondrial encephalomyopathies or cardiomyopathies, such as Leigh syndrome, and there are no cures for these types of disorders.”
Triple Proline Disrupts Protein Synthesis
Although several mitochondrial proteins contain two consecutive prolines, COX1 is the only one with a triple-proline motif, which interferes with ribosomal function and protein synthesis.
Under normal circumstances, ribosomes enlist helper proteins, called translation elongation factors, to grease the wheels and ensure proper synthesis. TACO1 is one of these helpers. When TACO1 is mutated, as it is in Leigh syndrome, ribosomes synthesize COX1 inefficiently, creating truncated, non-functioning proteins.
Karolinska Institute researchers Annika Krüger, Ph.D., and Joanna Rorbach, Ph.D., could see that the ribosomes pause when they find consecutive prolines but normally continue. But they have a hard time resuming protein synthesis when TACO1 is not functioning.
The condition stems from dysfunctional cytochrome c oxidase, the mitochondrial enzyme that contains COX1, so scientists initially believed the problem was isolated to that protein. But TACO1 performs its services for all mitochondrial proteins. COX1 just needs more help because it’s the only one with three consecutive prolines.
“The other mitochondrial proteins are not as difficult to synthesize, so TACO1’s status is less important. But because COX1 is so challenging to synthesize, losing TACO1 has disastrous consequences,” said Michele Brischigliaro, Ph.D., a postdoctoral fellow in the Barrientos laboratory and first author on the paper. Ahram Ahn, a student in the Miller School’s biochemistry and molecular biology graduate program, was also a co-author.
Having shown that TACO1 plays such as a vital role in general mitochondrial translation and prominently affects COX1 synthesis, the team is now dissecting how the protein interacts with mitochondrial ribosomes. They want to know if gene editing could disrupt the triple proline sequence that is causing so many problems.
“If we could eliminate the polyproline motif in COX1, the TACO1 loss of function would become mostly irrelevant,” said Dr. Barrientos. “It would require substituting another amino acid for one of the prolines, which is easier said than done. However, now that we understand the root problem, we are well-positioned to explore creative ways to restore COX1 function.”
Tags: biochemistry and molecular biology, Dr. Antoni Barrientos, Leigh syndrome, mitochondrial diseases