# MT-ND3

## Overview
The MT-ND3 gene is a mitochondrial gene that encodes the protein mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 3, a critical component of Complex I in the mitochondrial respiratory chain. This protein is a transmembrane subunit involved in the electron transport chain, facilitating the transfer of electrons from NADH to ubiquinone, a process essential for ATP production through oxidative phosphorylation. MT-ND3 is integral to the structure and function of Complex I, contributing to the maintenance of the proton gradient across the mitochondrial membrane, which is vital for cellular energy metabolism. Mutations in the MT-ND3 gene have been implicated in various mitochondrial disorders, including Leigh syndrome, highlighting its clinical significance (Babot2014ND3; Levy2013Long; Jin2018Mitochondrial).

## Structure
The MT-ND3 subunit is a component of mitochondrial complex I, which plays a crucial role in the electron transport chain. Structurally, MT-ND3 is part of the membrane arm of complex I and is involved in the active/deactive transition of the enzyme. This transition is significant for the regulation of complex I activity, particularly under varying oxygen conditions (Babot2014ND3).

The ND3 subunit contains a loop connecting the first and second transmembrane helices, which is critical for its function. This loop is involved in the interaction between the membrane arm and the peripheral arm of complex I, specifically connecting to the PSST subunit. The loop's structural integrity is essential for the catalytic mechanism of complex I (Galkin2008Identification).

Cysteine-39 within the ND3 subunit is a notable feature, as it becomes exposed in the de-active form of complex I, making it susceptible to chemical modifications. This exposure is linked to the regulation of the enzyme and its interaction with other molecules, such as thiol reagents and reactive oxygen species (Babot2014ND3).

Mutations in the ND3 subunit, particularly in regions important for catalysis, have been associated with mitochondrial diseases, highlighting its structural and functional significance (Fiedorczuk2018Mammalian).

## Function
The MT-ND3 gene encodes a subunit of Complex I, also known as NADH:ubiquinone oxidoreductase, which is a crucial component of the mitochondrial respiratory chain. This complex is embedded in the inner mitochondrial membrane and plays a vital role in oxidative phosphorylation, a process essential for ATP production. MT-ND3 is involved in the initial step of the electron transport chain, where it facilitates the transfer of electrons from NADH to ubiquinone (Jin2018Mitochondrial; Mukherjee2020Molecular). This electron transfer is coupled with the translocation of protons across the mitochondrial membrane, contributing to the maintenance of the proton gradient necessary for ATP synthesis (Mukherjee2020Molecular).

In healthy human cells, MT-ND3 is part of the ND2 module within Complex I, which is essential for the proper assembly and function of the complex. This assembly is critical for efficient electron transport and energy production in mitochondria (Mukherjee2020Molecular). The activity of MT-ND3 and its role in maintaining mitochondrial function are crucial for cellular energy metabolism and overall organismal energy homeostasis (Smullen2023Modeling).

## Clinical Significance
Mutations in the MT-ND3 gene are associated with several mitochondrial disorders, most notably Leigh syndrome and mitochondrial encephalomyopathy. The m.10191T>C mutation in MT-ND3 is linked to Leigh syndrome, a severe neurological disorder characterized by progressive encephalomyopathy and bilateral focal lesions in the brain. This mutation results in a serine-to-proline substitution at position 45, disrupting a crucial transmembrane alpha helix domain in complex I of the mitochondrial respiratory chain, leading to a significant reduction in complex I activity (LeshinskySilver2005Fulminant; Levy2013Long). 

Patients with this mutation exhibit a range of clinical phenotypes, from infantile Leigh syndrome to adult-onset symptoms, including epilepsy, stroke-like episodes, optic atrophy, and cognitive decline (Na2021Association; Malfatti2007Novel). The mutation's impact on complex I function is thought to impair electron transport and enzyme stability, contributing to the disease's severity (LeshinskySilver2005Fulminant). 

Alterations in MT-ND3 expression levels have also been linked to hepatic steatosis, where increased expression correlates with the severity of the condition, suggesting a role in disease progression (Wang2013Highly).

## Interactions
MT-ND3 is a subunit of mitochondrial complex I, also known as NADH:ubiquinone oxidoreductase, which is a large multi-subunit transmembrane protein complex involved in electron transfer and proton translocation. Within complex I, MT-ND3 is part of the ND2 module, which also includes subunits MT-ND6 and MT-ND4L, along with other nuclear DNA-encoded subunits (Mukherjee2020Molecular). The ND3 subunit undergoes conformational changes during the transition from the active (A) form to the de-active (D) form of complex I. In the D-form, the ND3 subunit's cysteine residue (Cys-39) becomes exposed, making it susceptible to covalent modification, which suggests structural rearrangements within the complex (Babot2014ND3).

The ND3 subunit is more exposed in the D-form of complex I, indicating a significant region becomes accessible during deactivation. This exposure allows for potential interactions with other subunits, such as the 39 kDa subunit (NDUFA9), which can be crosslinked with ND3 only in the D-form, suggesting a possible interaction or structural rearrangement between these subunits (Babot2014ND3). These interactions and structural changes are crucial for understanding the functional dynamics of complex I and its role in mitochondrial respiration.


## References


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