# GFM1

## Overview
The GFM1 gene encodes the mitochondrial elongation factor G1 (EFG1), a GTPase that plays a pivotal role in mitochondrial protein synthesis. EFG1 is integral to the translocation step of mitochondrial translation, facilitating the movement of peptidyl-tRNA from the ribosomal A site to the P site, a critical process for the synthesis of proteins encoded by mitochondrial DNA. These proteins are essential components of the oxidative phosphorylation system, which is the primary energy-generating process in cells (You2020A; Su2020Clinical). The protein consists of 751 amino acids and includes five Pfam domains, with a crucial GTP-binding domain that mediates conformational changes necessary for its function (Su2020Clinical). Mutations in GFM1 can lead to severe mitochondrial disorders, underscoring its importance in maintaining mitochondrial function and energy production (Ravn2015Neonatal; Smits2010Mutation).

## Structure
The GFM1 gene encodes the mitochondrial elongation factor G1 (EFG1) protein, which is a GTPase involved in mitochondrial translation. The protein consists of 751 amino acids and includes five Pfam domains, with a significant role in the translocation step of protein synthesis within mitochondria (Balasubramaniam2011Infantile; Su2020Clinical). The GTP-binding domain is crucial for its function, facilitating the movement of peptidyl-tRNA from the ribosomal A site to the P site after peptide bond formation (Su2020Clinical).

Mutations in GFM1 can lead to structural changes that affect its function. For instance, a mutation resulting in a premature stop codon at position 526 leads to the loss of domains IV and V, which are essential for tRNA-mRNA movement (Su2020Clinical). Another mutation, Arg250Trp, affects the G' subdomain, disrupting stabilizing hydrogen bonds and interactions with other proteins, which impairs ribosome-dependent GTP hydrolysis (Smits2010Mutation).

The protein's structure is modeled based on the crystal structure of Thermus thermophilus EFG, with which it shares 45% sequence identity, although the first 43 residues of EFG1 could not be modeled (Smits2010Mutation).

## Function
The GFM1 gene encodes the mitochondrial elongation factor G1 (EFG1), a GTPase that plays a crucial role in mitochondrial protein synthesis. In healthy human cells, EFG1 is involved in the translocation of peptidyl-tRNA from the ribosomal A site to the P site during the elongation phase of mitochondrial translation. This process is essential for the synthesis of proteins encoded by mitochondrial DNA, which are critical components of the oxidative phosphorylation (OXPHOS) system, the primary energy-generating process in cells (You2020A; Su2020Clinical).

EFG1 interacts with the 50S large ribosomal subunit, facilitating the movement of tRNA and mRNA, which is necessary for the continuation of protein synthesis. The protein consists of 751 amino acids and includes five Pfam domains, with the GTP-binding domain I being involved in conformational changes mediated by GTP hydrolysis (Su2020Clinical). The proper function of GFM1 is essential for maintaining mitochondrial function and energy production, as it ensures the correct assembly and activity of OXPHOS complexes (Brito2015Longterm; Smits2010Mutation). EFG1 is active in the mitochondrial matrix, where it supports the production of proteins necessary for cellular energy metabolism (SuárezRivero2022UPRmt).

## Clinical Significance
Mutations in the GFM1 gene are associated with a range of severe mitochondrial disorders, primarily affecting the nervous system and liver. These mutations can lead to combined oxidative phosphorylation deficiency diseases, which manifest with symptoms such as seizures, hepatomegaly, mental retardation, and lactic acidosis (You2020A). Neonatal mitochondrial hepatoencephalopathy is another condition linked to GFM1 mutations, characterized by severe liver dysfunction, lactic acidosis, and neurological impairments, often resulting in early fatal outcomes (Ravn2015Neonatal).

Patients with GFM1 mutations may present with a variety of clinical symptoms, including developmental delays, epilepsy, and metabolic acidosis. These symptoms are often accompanied by reduced activities of mitochondrial respiratory chain complexes, particularly complexes I, III, and IV (Balasubramaniam2011Infantile; Smits2010Mutation). The mutations can result in decreased expression levels of mitochondrial proteins, affecting mitochondrial function and leading to severe phenotypes (Su2020Clinical).

The clinical presentation of GFM1-related disorders can vary significantly, with some patients exhibiting predominantly neurological symptoms, while others show more pronounced liver involvement (Barcia2019Clinical). The prognosis for these conditions is generally poor, highlighting the need for further research to develop effective treatments (You2020A).

## Interactions
GFM1, a mitochondrial translation elongation factor, is involved in several interactions crucial for mitochondrial function. It interacts with mitoribosomes to facilitate the translocation step during protein synthesis. This interaction is essential for the proper functioning of the mitochondrial translation machinery (Brito2015Longterm).

GFM1 is also associated with ClpX, a component of the mitochondrial matrix AAA+ unfoldase complex. This interaction is significant in the context of ClpP inactivity, where GFM1 accumulates alongside ClpX, potentially affecting mitochondrial RNA granules and tRNA maturation (Auburger2022The; Key2021Inactivity). The accumulation of GFM1 in the absence of ClpP suggests its role in mitoribosomal translation and its potential impact on cellular processes when dysregulated (Key2021Inactivity).

Additionally, GFM1's interaction with ribosomal protein L7/L12 is crucial for ribosome-activated GTP hydrolysis, a process impaired by certain mutations in GFM1, such as the Arg250Trp mutation. This mutation disrupts the protein's structure and interactions, leading to mitochondrial translation defects (Smits2010Mutation). These interactions highlight GFM1's role in maintaining mitochondrial protein synthesis and its involvement in broader mitochondrial processes.


## References


[1. (You2020A) Cuiping You, Na Xu, Shiyan Qiu, Yufen Li, Liyun Xu, Xia Li, and Li Yang. A novel composition of two heterozygous gfm1 mutations in a chinese child with epilepsy and mental retardation. Brain and Behavior, August 2020. URL: http://dx.doi.org/10.1002/brb3.1791, doi:10.1002/brb3.1791. This article has 6 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/brb3.1791)

2. (Auburger2022The) The Bacterial ClpXP-ClpB Family is Enriched with RNA-Binding Protein Complexes. This article has 5 citations.

[3. (Key2021Inactivity) Jana Key, Sylvia Torres-Odio, Nina C. Bach, Suzana Gispert, Gabriele Koepf, Marina Reichlmeir, A. Phillip West, Holger Prokisch, Peter Freisinger, William G. Newman, Stavit Shalev, Stephan A. Sieber, Ilka Wittig, and Georg Auburger. Inactivity of peptidase clpp causes primary accumulation of mitochondrial disaggregase clpx with its interacting nucleoid proteins, and of mtdna. Cells, 10(12):3354, November 2021. URL: http://dx.doi.org/10.3390/cells10123354, doi:10.3390/cells10123354. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/cells10123354)

[4. (Ravn2015Neonatal) Kirstine Ravn, Bitten Schönewolf-Greulich, Rikke M. Hansen, Anna-Helene Bohr, Morten Duno, Flemming Wibrand, and Elsebet Ostergaard. Neonatal mitochondrial hepatoencephalopathy caused by novel gfm1 mutations. Molecular Genetics and Metabolism Reports, 3:5–10, June 2015. URL: http://dx.doi.org/10.1016/j.ymgmr.2015.01.004, doi:10.1016/j.ymgmr.2015.01.004. This article has 10 citations and is from a poor quality or predatory journal.](https://doi.org/10.1016/j.ymgmr.2015.01.004)

[5. (Su2020Clinical) Chang Su and Fangfang Wang. Clinical and molecular findings in a family expressing a novel heterozygous variant of the g elongation factor mitochondrial 1 gene. Experimental and Therapeutic Medicine, 20(6):1–1, October 2020. URL: http://dx.doi.org/10.3892/etm.2020.9303, doi:10.3892/etm.2020.9303. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.3892/etm.2020.9303)

[6. (Brito2015Longterm) Sara Brito, Kyle Thompson, Jaume Campistol, Jaime Colomer, Steven A. Hardy, Langping He, Ana Fernández-Marmiesse, Lourdes Palacios, Cristina Jou, Cecilia Jiménez-Mallebrera, Judith Armstrong, Raquel Montero, Rafael Artuch, Christin Tischner, Tina Wenz, Robert McFarland, and Robert W. Taylor. Long-term survival in a child with severe encephalopathy, multiple respiratory chain deficiency and gfm1 mutations. Frontiers in Genetics, March 2015. URL: http://dx.doi.org/10.3389/fgene.2015.00102, doi:10.3389/fgene.2015.00102. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fgene.2015.00102)

[7. (SuárezRivero2022UPRmt) Juan M. Suárez-Rivero, Carmen J. Pastor-Maldonado, Suleva Povea-Cabello, Mónica Álvarez-Córdoba, Irene Villalón-García, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Manuel Munuera-Cabeza, Diana Reche-López, Paula Cilleros-Holgado, Rocío Piñero-Perez, and José A. Sánchez-Alcázar. Uprmt activation improves pathological alterations in cellular models of mitochondrial diseases. Orphanet Journal of Rare Diseases, May 2022. URL: http://dx.doi.org/10.1186/s13023-022-02331-8, doi:10.1186/s13023-022-02331-8. This article has 15 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s13023-022-02331-8)

[8. (Balasubramaniam2011Infantile) S. Balasubramaniam, Y. S. Choy, A. Talib, M. D. Norsiah, L. P. van den Heuvel, and R. J. Rodenburg. Infantile Progressive Hepatoencephalomyopathy with Combined OXPHOS Deficiency due to Mutations in the Mitochondrial Translation Elongation Factor Gene GFM1, pages 113–122. Springer Berlin Heidelberg, 2011. URL: http://dx.doi.org/10.1007/8904_2011_107, doi:10.1007/8904_2011_107. This article has 16 citations.](https://doi.org/10.1007/8904_2011_107)

[9. (Barcia2019Clinical) Giulia Barcia, Marlène Rio, Zahra Assouline, Coralie Zangarelli, Naig Gueguen, Valerie D. Dumas, Pascale Marcorelles, Manuel Schiff, Abdelhamid Slama, Magalie Barth, Marie Hully, Pascale Lonlay, Arnold Munnich, Isabelle Desguerre, Jean‐Paul Bonnefont, Julie Steffann, Vincent Procaccio, Nathalie Boddaert, Agnès Rötig, Metodi D. Metodiev, and Benedetta Ruzzenente. Clinical, neuroimaging and biochemical findings in patients and patient fibroblasts expressing ten novel gfm1 mutations. Human Mutation, 41(2):397–402, November 2019. URL: http://dx.doi.org/10.1002/humu.23937, doi:10.1002/humu.23937. This article has 11 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/humu.23937)

[10. (Smits2010Mutation) Paulien Smits, Hana Antonicka, Peter M van Hasselt, Woranontee Weraarpachai, Wolfram Haller, Marieke Schreurs, Hanka Venselaar, Richard J Rodenburg, Jan A Smeitink, and Lambert P van den Heuvel. Mutation in subdomain g’ of mitochondrial elongation factor g1 is associated with combined oxphos deficiency in fibroblasts but not in muscle. European Journal of Human Genetics, 19(3):275–279, December 2010. URL: http://dx.doi.org/10.1038/ejhg.2010.208, doi:10.1038/ejhg.2010.208. This article has 41 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/ejhg.2010.208)