# NDUFA1

## Overview
The NDUFA1 gene encodes the NADH:ubiquinone oxidoreductase subunit A1, a crucial component of mitochondrial complex I, which is the first enzyme in the electron transport chain. This protein, also known as the MWFE protein, is integral to the inner mitochondrial membrane and plays a vital role in the assembly and stability of complex I, facilitating the transfer of electrons from NADH to ubiquinone. The NDUFA1 gene is highly conserved across species, underscoring its essential function in cellular energy production (Fernandez‐Moreira2007X‐linked; Au1999The). Mutations in NDUFA1 can lead to complex I deficiencies, resulting in various mitochondrial disorders characterized by impaired energy metabolism, such as mitochondrial encephalomyopathy and Leigh syndrome (Fernandez‐Moreira2007X‐linked; Potluri2009A).

## Structure
The NDUFA1 gene encodes a small integral membrane protein known as the MWFE protein, which consists of 70 amino acids (Au1999The). The primary structure of the MWFE protein includes a hydrophobic N-terminal domain and a hydrophilic, positively charged C-terminal domain, suggesting its association with the integral membrane fraction of complex I (Au1999The). The protein is highly conserved across species, indicating its essential role in mitochondrial function (Fernandez‐Moreira2007X‐linked).

The MWFE protein is a component of mitochondrial complex I, which is the largest complex in the mitochondrial respiratory chain. Complex I has an L-shaped structure with a membrane arm embedded in the inner mitochondrial membrane and a peripheral arm protruding into the matrix (Fernandez‐Moreira2007X‐linked). The NDUFA1 protein is involved in the assembly and stability of complex I, interacting with other subunits to maintain its function (Potluri2009A).

Mutations in the NDUFA1 gene, such as G32R, can significantly affect the protein's interaction with other complex I subunits, leading to reduced complex I activity and associated mitochondrial diseases (Potluri2009A). The protein does not require proteolytic processing for mitochondrial import (Au1999The).

## Function
The NDUFA1 gene encodes a subunit of complex I, also known as NADH:ubiquinone oxidoreductase, which is a crucial component of the mitochondrial electron transport chain. This complex is responsible for transferring electrons from NADH to ubiquinone, a process that is coupled with the translocation of protons across the inner mitochondrial membrane. This proton gradient is then utilized by ATP synthase to generate ATP, the primary energy currency of the cell (Fernandez‐Moreira2007X‐linked; Wittig2001Sequence).

The NDUFA1 gene product, known as the MWFE protein, is essential for the activity of complex I in mammalian mitochondria. It plays a critical role in the assembly and stability of complex I, ensuring its proper function. The MWFE protein is characterized by a highly hydrophobic N-terminal domain and a hydrophilic, positively charged C-terminal domain, suggesting its association with the integral membrane fraction of complex I (Au1999The).

Mutations in the NDUFA1 gene can lead to complex I deficiencies, which are associated with various mitochondrial disorders. These deficiencies can result in a range of clinical symptoms, including neurological disorders and myopathy, due to impaired energy production (Fernandez‐Moreira2007X‐linked; Potluri2009A).

## Clinical Significance
Mutations in the NDUFA1 gene are associated with several mitochondrial disorders, primarily affecting the mitochondrial complex I, a crucial component of the oxidative phosphorylation pathway. These mutations can lead to complex I deficiency, which is linked to a range of clinical conditions, including mitochondrial encephalomyopathy and Leigh syndrome. Patients with these conditions often exhibit symptoms such as neurodegeneration, muscle weakness, seizures, sensorineural hearing loss, and developmental delays (Fernandez‐Moreira2007X‐linked; Potluri2009A).

Specific mutations, such as the missense mutation G32R, have been identified in patients with progressive neurodegenerative diseases. This mutation results in a significant decrease in complex I assembly and activity, contributing to the disease phenotype (Potluri2009A). Other mutations, like G8R and R37S, have also been linked to complex I deficiency and mitochondrial dysfunction, affecting the stability and assembly of the complex (Fernandez‐Moreira2007X‐linked).

In some cases, heterozygous mutations in NDUFA1 have been reported in females, suggesting that X-inactivation patterns may influence the clinical expression of the disease (Mayr2011Heterozygous). These findings underscore the critical role of NDUFA1 in maintaining mitochondrial function and its impact on human health when mutated.

## Interactions
The NDUFA1 protein, a subunit of mitochondrial complex I, is involved in several critical interactions within the electron transport chain. It directly interacts with mtDNA-encoded subunits ND1 and ND4, as confirmed by yeast two-hybrid experiments, which demonstrated growth in restrictive media when NDUFA1 was present with these subunits (Gershoni2010Coevolution). These interactions are essential for the assembly of the membrane arm of complex I, highlighting the role of NDUFA1 in maintaining the structural integrity and function of the complex (Gershoni2010Coevolution).

NDUFA1 is also implicated in the formation of supercomplexes, as mutations in this gene can affect the assembly and stability of complex I. For instance, a mutation in NDUFA1 led to altered incorporation of subunits into complex I, suggesting its involvement in the formation of supercomplexes I1III2 or I1III2IV1 (Fernandez‐Moreira2007X‐linked). These interactions underscore the importance of NDUFA1 in the proper functioning of mitochondrial complex I and its potential impact on mitochondrial diseases when disrupted.


## References


[1. (Mayr2011Heterozygous) Johannes A. Mayr, Olaf Bodamer, Tobias B. Haack, Franz A. Zimmermann, Florence Madignier, Holger Prokisch, Christian Rauscher, Johannes Koch, and Wolfgang Sperl. Heterozygous mutation in the x chromosomal ndufa1 gene in a girl with complex i deficiency. Molecular Genetics and Metabolism, 103(4):358–361, August 2011. URL: http://dx.doi.org/10.1016/j.ymgme.2011.04.010, doi:10.1016/j.ymgme.2011.04.010. This article has 18 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ymgme.2011.04.010)

[2. (Potluri2009A) Prasanth Potluri, Antonio Davila, Eduardo Ruiz-Pesini, Dan Mishmar, Sean O’Hearn, Saege Hancock, Mariella Simon, Immo E. Scheffler, Douglas C. Wallace, and Vincent Procaccio. A novel ndufa1 mutation leads to a progressive mitochondrial complex i-specific neurodegenerative disease. Molecular Genetics and Metabolism, 96(4):189–195, April 2009. URL: http://dx.doi.org/10.1016/j.ymgme.2008.12.004, doi:10.1016/j.ymgme.2008.12.004. This article has 82 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ymgme.2008.12.004)

[3. (Wittig2001Sequence) I. Wittig, P. Augstein, G. K. Brown, T. Fujii, A. Rötig, P. Rustin, A. Munnich, P. Seibel, D. Thorburn, B. Wissinger, K. Tamboom, A. Metspalu, E. Lamantea, M. Zeviani, and M. S. Wehnert. Sequence variations in the ndufa1 gene encoding a subunit of complex i of the respiratory chain. Journal of Inherited Metabolic Disease, 24(1):15–27, February 2001. URL: http://dx.doi.org/10.1023/A:1005638218246, doi:10.1023/a:1005638218246. This article has 16 citations and is from a peer-reviewed journal.](https://doi.org/10.1023/A:1005638218246)

[4. (Au1999The) Harry C. Au, Byoung Boo Seo, Akemi Matsuno-Yagi, Takao Yagi, and Immo E. Scheffler. The ndufa1 gene product (mwfe protein) is essential for activity of complex i in mammalian mitochondria. Proceedings of the National Academy of Sciences, 96(8):4354–4359, April 1999. URL: http://dx.doi.org/10.1073/pnas.96.8.4354, doi:10.1073/pnas.96.8.4354. This article has 64 citations.](https://doi.org/10.1073/pnas.96.8.4354)

[5. (Gershoni2010Coevolution) Moran Gershoni, Angelika Fuchs, Naama Shani, Yearit Fridman, Marisol Corral-Debrinski, Amir Aharoni, Dmitrij Frishman, and Dan Mishmar. Coevolution predicts direct interactions between mtdna-encoded and ndna-encoded subunits of oxidative phosphorylation complex i. Journal of Molecular Biology, 404(1):158–171, November 2010. URL: http://dx.doi.org/10.1016/j.jmb.2010.09.029, doi:10.1016/j.jmb.2010.09.029. This article has 57 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.jmb.2010.09.029)

[6. (Fernandez‐Moreira2007X‐linked) Daniel Fernandez‐Moreira, Cristina Ugalde, Roel Smeets, Richard J. T. Rodenburg, Eduardo Lopez‐Laso, Maria L. Ruiz‐Falco, Paz Briones, Miguel A. Martin, Jan A. M. Smeitink, and Joaquín Arenas. X‐linked ndufa1 gene mutations associated with mitochondrial encephalomyopathy. Annals of Neurology, 61(1):73–83, January 2007. URL: http://dx.doi.org/10.1002/ana.21036, doi:10.1002/ana.21036. This article has 106 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1002/ana.21036)