Structure
The ''MT-ND4L'' gene is located in human mitochondrial DNA from base pair 10,469 to 10,765.''Homo sapiens'' mitochondrion, complete genomeCAA TGC TAA
-3' coding for Gln, Cys and Stop) with the first three codons of the '' MT-ND4'' gene (5'-ATG CTA AAA
-3' coding for amino acids Met-Leu-Lys). With respect to the ''MT-ND4L'' AATGC] AAA
versus CA TGCTA] AA/code>.
Function
The MT-ND4L product is a subunit of the respiratory chain Complex I
Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes th ...
that is believed to belong to the minimal assembly of core proteins required to catalyze NADH
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...
dehydrogenation and electron transfer
Electron transfer (ET) occurs when an electron relocates from an atom, ion, or molecule, to another such chemical entity. ET describes the mechanism by which electrons are transferred in redox reactions.
Electrochemical processes are ET reactio ...
to ubiquinone
Coenzyme Q10 (CoQ10 ), also known as ubiquinone, is a naturally occurring Cofactor (biochemistry), biochemical cofactor (coenzyme) and an antioxidant produced by the human body. It can also be obtained from dietary sources, such as meat, fish, ...
(coenzyme Q10). Initially, NADH
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...
binds to Complex I and transfers two electrons to the isoalloxazine ring
Flavins (from Latin ''flavus'', "yellow") refers generally to the class of organic compounds containing the tricyclic heterocycle isoalloxazine or its isomer alloxazine, and derivatives thereof. The biochemical source of flavin is the yellow B v ...
of the flavin mononucleotide
Flavin mononucleotide (FMN), or riboflavin-5′-phosphate, is a biomolecule produced from riboflavin (vitamin B2) by the enzyme riboflavin kinase and functions as the prosthetic group of various oxidoreductases, including NADH dehydrogenase, as ...
(FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol
A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans.
The natural ubiquinol form of coenzyme Q is 2,3-dimethoxy-5-methyl-6-poly p ...
(CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and p''K'' shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.
Clinical significance
Mitochondrial dysfunction resulting from variants of MT-ND4L, MT-ND1 and MT-ND2 have been linked to BMI in adults and implicated in metabolic disorders including obesity, diabetes and hypertension.
A T>C mutation at position 10,663 in the mitochondrial gene MT-ND4L is known to cause Leber's Hereditary Optic Neuropathy
Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; it predomin ...
(LHON). This mutation results in the replacement of the amino acid valine with alanine at position 65 of the protein ND4L, disrupting function of Complex I
Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes th ...
in the electron transport chain
An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
. It is unknown how this mutation leads to the loss of vision in LHON patients, but it may interrupt ATP production due to the impaired activity of Complex I
Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes th ...
. Mutations in other genes encoding subunits of Complex I
Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes th ...
, including MT-ND1, MT-ND2, MT-ND4, MT-ND5, and MT-ND6 are also known to cause LHON.
References
Further reading
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External links
Mass spectrometry characterization of MT-ND4L at COPaKB
{{Mitochondrial enzymes
Proteins
Human mitochondrial genes