Researchers found that a mutation in the ribosomal protein RPL3L, expressed only in heart and skeletal muscle, reduce cardiac contractility in mice. The team found that as the mutant RPL3L reads mRNA it would delay translation for the amino acids proline and alanine. This delay caused ribosomes to collide along the mRNA resulting in misfolded proteins that would be cleared out from the cell. While the deficiency altered translation dynamics for the entire tissue, its effects were most pronounced for proteins related cardiac muscle contraction.
The echocardiogram of RPL3L mutant mice compared to control mice shows that the knockout mice have a smaller difference between LVDd and LVDs, indicating reduced cardiac contractility.
The team's analysis revealed that RPL3L-deficient hearts exhibited delayed translation rates at proline and alanine codons on mRNA. This 'translational traffic jam' resulted in misfolded proteins which would be cleared by the cell's quality control system. Many of the genes with abnormal translation rates were found to be related to heart contraction.
Newswise — Fukuoka, Japan— Fukuoka, Japan—A group of scientists have found that a mutation in a ribosomal protein detected exclusively in heart and skeletal muscle results in diminished cardiac contractility in mice.
The identified mutation caused a delay in mRNA translation, resulting in ribosomal collisions and consequent protein folding irregularities. These aberrant proteins were subsequently subjected to degradation by the cell's quality control mechanism. Additionally, although the deficiency in the ribosomal protein, referred to as RPL3L, affected translation dynamics throughout the tissue, its impact was particularly significant for proteins associated with cardiac muscle contraction.
The research, featured in the journal Nature Communications, provides valuable insights into the intricate workings of ribosomes, a highly fundamental molecule. Moreover, considering that deficiencies in the RPL3L gene have been observed in individuals afflicted with cardiomyopathy and atrial fibrillation, the team envisions that their novel discoveries could pave the way for prospective therapeutic approaches in the future.
It's probable that you're acquainted with the cellular process of protein and molecule production, which is crucial for the proper functioning of the body. DNA undergoes transcription to generate messenger RNA (mRNA), serving as a blueprint for connecting amino acids and constructing proteins. The ribosome, at the core of this protein synthesis process, interprets the mRNA code and transforms it into proteins.
Due to their essential role, ribosomes are present in all cells and were traditionally believed to be largely uniform. However, recent investigations have unveiled variations in ribosomal structures, challenging the notion of their uniformity.
"Ribosome heterogeneity," as elucidated by Keiichi I. Nakayama from Kyushu University's Medical Institute of Bioregulation, refers to the observed structural differences in ribosomes that contribute to translation specificity. For instance, certain ribosomes demonstrate a higher proficiency in generating proteins involved in regulating metabolism or the cell cycle. Nakayama, leading the study, introduced this novel concept. The team hypothesized that such heterogeneity would exist among different tissues. Through an analysis of tissue-specific ribosomal proteins, they identified a particular protein, RPL3L, which was exclusively expressed in the heart and skeletal muscle.
To comprehend the role of RPL3L, the researchers examined the hearts of mice possessing a mutated RPL3L gene. Consistent with their expectations, echocardiographic analysis revealed a decline in cardiac contractility among these mice. The subsequent phase of their investigation aimed to unveil the precise mechanism through which this mutation triggered such a condition. It was discovered that the RPL3L mutation caused a disruption in the translation process, leading to a "translational traffic jam" specifically affecting proteins crucial for normal heart function.
Nakayama further explains, "Through our investigations, we determined that the mutated RPL3L gene led to a delay in the translation process specifically for the proline and alanine codons present on mRNA. This delay caused collisions between ribosomes, leading to improper folding of proteins." He continues, "Consequently, the cell's quality control system recognized these misfolded proteins and eliminated them. Significantly, a substantial portion of the misfolded proteins were directly associated with cardiac contraction."
By delving into the intricacies of ribosomal translation dynamics, particularly those involving RPL3L, the team aspires to enhance our comprehension of how genetic mutations in this ribosomal protein contribute to heart diseases such as dilated cardiomyopathy and atrial fibrillation, as observed in affected patients. This deeper understanding holds the potential to shed light on the underlying mechanisms of these conditions, ultimately paving the way for improved diagnosis, treatment, and management strategies.
Nakayama concludes by emphasizing the continuous progress being made in the realms of biology and medicine, even in areas as fundamental as ribosomes. He expresses enthusiasm about the future discoveries that lie ahead, highlighting the dynamic and ever-evolving nature of scientific exploration.
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For more information about this research, see "RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function," Chisa Shiraishi, Akinobu Matsumoto, Kazuya Ichihara, Taishi Yamamoto, Takeshi Yokoyama, Taisuke Mizoo, Atsushi Hatano, Masaki Matsumoto, Yoshikazu Tanaka, Eriko Matsuura-Suzuki, Shintaro Iwasaki, Shouji Matsushima, Hiroyuki Tsutsui, Keiichi I. Nakayama Nature Communications, https://doi.org/10.1038/s41467-023-37838-6
About Kyushu University
Kyushu University is one of Japan's leading research-oriented institutes of higher education since its founding in 1911. Home to around 19,000 students and 8,000 faculty and staff, Kyushu U's world-class research centers cover a wide range of study areas and research fields, from the humanities and arts to engineering and medical sciences. Its multiple campuses—including one of the largest in Japan—are located around Fukuoka City, a coastal metropolis on the southwestern Japanese island of Kyushu that is frequently ranked among the world's most livable cities and historically known as Japan's gateway to Asia. Through its Vision 2030, Kyushu U will 'Drive Social Change with Integrative Knowledge.' Its synergistic application of knowledge will encompass all of academia and solve issues in society while innovating new systems for a better future.
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Credit: Kyushu University/Nakayama Lab
Caption: Researchers found that a mutation in the ribosomal protein RPL3L, expressed only in heart and skeletal muscle, reduce cardiac contractility in mice. The team found that as the mutant RPL3L reads mRNA it would delay translation for the amino acids proline and alanine. This delay caused ribosomes to collide along the mRNA resulting in misfolded proteins that would be cleared out from the cell. While the deficiency altered translation dynamics for the entire tissue, its effects were most pronounced for proteins related cardiac muscle contraction.
Credit: Kyushu University/Nakayama Lab
Caption: The echocardiogram of RPL3L mutant mice compared to control mice shows that the knockout mice have a smaller difference between LVDd and LVDs, indicating reduced cardiac contractility.
Credit: Kyushu University/Nakayama Lab
Caption: The team's analysis revealed that RPL3L-deficient hearts exhibited delayed translation rates at proline and alanine codons on mRNA. This 'translational traffic jam' resulted in misfolded proteins which would be cleared by the cell's quality control system. Many of the genes with abnormal translation rates were found to be related to heart contraction.
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