Mitochondrial Protein FAM210A Regulates Muscle Growth and Protein Synthesis Through Metabolic Crosstalk

Centrala begrepp

Mitochondrial protein FAM210A is essential for maintaining mitochondrial integrity and metabolism, which in turn regulates cytosolic protein translation and muscle growth.

Sammanfattning

The study investigates the role of the mitochondrial protein FAM210A in regulating skeletal muscle growth and homeostasis. Key highlights:

FAM210A expression is positively correlated with muscle mass in mice and humans. Muscle-specific deletion of Fam210a in mice leads to progressive muscle atrophy, weakness, and premature death.

Fam210a knockout disrupts mitochondrial cristae structure, reduces mitochondrial density and function, and reverses the TCA cycle towards the reductive direction, resulting in acetyl-CoA accumulation.

The increased acetyl-CoA causes hyperacetylation of cytosolic ribosomal proteins, leading to ribosomal disassembly and translational defects. Transplantation of Fam210a-null mitochondria into wildtype myoblasts is sufficient to induce protein hyperacetylation.

The study reveals a novel crosstalk between mitochondria and ribosomes mediated by FAM210A, which is essential for maintaining muscle protein synthesis and growth.

Statistik

Fam210a mRNA level is reduced by 37% in old vs young human skeletal muscle.
Fam210a mRNA level is reduced by 33% in vastus lateralis muscle after 48 hours of knee immobilization.
Fam210a mRNA level is reduced by 18.6% in Pompe disease patients and 42% in Duchenne Muscular Dystrophy patients compared to healthy controls.
Fam210a mRNA level is increased by 21.5% in myostatin knockout mouse muscle.

Citat

"Skeletal muscle growth and hypertrophy are contributed by the accretion of myonuclei from differentiated muscle stem cells (satellite cells) at early stages and by protein synthesis in the existing myofibers after the myonuclei addition ceases."
"Understanding the mechanisms that regulate muscle growth provides potential strategies to boost muscle health for the improvement of life qualities."
"These results uncover a novel role of FAM210A in regulating mitochondria metabolism and provide evidence linking metabolic inputs to the regulation of skeletal muscle growth and atrophy through protein acetylation."

Viktiga insikter från

FAM210A mediates an inter-organelle crosstalk essential for protein synthesis and muscle growth in mouse

by Chen,J., Yue... på www.biorxiv.org 08-04-2023

https://www.biorxiv.org/content/10.1101/2023.08.03.551853v2

Djupare frågor

How does the mitochondrial metabolic state influence other cellular processes beyond protein synthesis, such as signaling pathways or organelle dynamics

The mitochondrial metabolic state plays a crucial role in influencing various cellular processes beyond protein synthesis. One significant aspect is the impact on signaling pathways. Mitochondria are known to produce reactive oxygen species (ROS) as byproducts of oxidative phosphorylation. Changes in mitochondrial metabolism can lead to alterations in ROS production, which in turn can modulate signaling pathways involved in cell survival, proliferation, and apoptosis. Additionally, metabolites generated in the TCA cycle, such as citrate and succinate, can act as signaling molecules to regulate gene expression and cellular responses.
Moreover, mitochondrial metabolism is closely linked to organelle dynamics. Mitochondria participate in calcium signaling, which is essential for various cellular processes. Changes in mitochondrial calcium levels can affect organelle dynamics, including mitochondrial fusion and fission. Furthermore, mitochondria play a role in lipid metabolism and the production of metabolites that regulate lipid droplet dynamics and cellular lipid homeostasis. Disruptions in mitochondrial metabolism can lead to alterations in lipid droplet formation and turnover, impacting cellular functions.

What are the potential therapeutic implications of targeting the FAM210A-mediated mitochondria-ribosome crosstalk for muscle wasting disorders

Targeting the FAM210A-mediated mitochondria-ribosome crosstalk holds significant therapeutic implications for muscle wasting disorders. By understanding how FAM210A regulates mitochondrial metabolism and protein acetylation, potential therapeutic strategies can be developed to modulate this pathway. One approach could involve developing small molecules or gene therapies to enhance FAM210A expression or activity in muscle cells, thereby restoring mitochondrial function and protein synthesis.
Additionally, targeting the downstream effects of FAM210A deficiency, such as protein hyperacetylation and translational defects, could be a viable therapeutic strategy. Modulating the acetylation status of ribosomal proteins or enhancing protein translation in muscle cells could help counteract the muscle atrophy observed in conditions where FAM210A is deficient.
Overall, interventions aimed at restoring the balance of mitochondrial metabolism and protein synthesis through the FAM210A pathway have the potential to mitigate muscle wasting disorders and improve muscle health and function.

Given the integral crosstalk between bone and muscle, how might the FAM210A-dependent regulation of muscle metabolism impact bone homeostasis

The regulation of muscle metabolism by FAM210A could have significant implications for bone homeostasis due to the integral crosstalk between bone and muscle tissues. The expression of FAM210A has been correlated with bone density and muscle mass, suggesting a potential role in coordinating the growth and maintenance of both tissues.
Disruptions in FAM210A-mediated mitochondrial metabolism in muscle could impact the secretion of myokines and other factors that influence bone health. For example, changes in muscle mass and function due to FAM210A deficiency may alter the mechanical loading on bones, affecting bone density and strength. Additionally, alterations in systemic metabolism and signaling pathways resulting from muscle wasting could indirectly impact bone remodeling and mineralization.
Therefore, targeting the FAM210A-dependent regulation of muscle metabolism could have implications for maintaining bone homeostasis and overall musculoskeletal health. Developing therapies that modulate FAM210A activity or its downstream effects may offer a novel approach to addressing conditions that affect both muscle and bone tissues.