MT-ND1
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MT-ND1 is a
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
of the
mitochondrial genome Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial D ...
coding for the NADH-ubiquinone oxidoreductase chain 1 (ND1)
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
. The ND1 protein is a subunit of
NADH dehydrogenase NADH dehydrogenase is an enzyme that converts nicotinamide adenine dinucleotide (NAD) from its reduced form (NADH) to its oxidized form (NAD+). Members of the NADH dehydrogenase family and analogues are commonly systematically named using the for ...
, which is located in the
mitochondrial inner membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. ...
and is the largest of the five complexes of the
electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
. Variants of the human MT-ND1 gene are associated with
mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD (maternally inherited diabetes and deafness, MERRF syndrome, and Leber's hereditary optic neu ...
(MELAS),
Leigh's syndrome Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fir ...
(LS),
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) and increases in adult BMI.


Structure

MT-ND1 is located in mitochondrial DNA from base pair 3,307 to 4,262. The MT-ND1 gene produces a 36 kDa protein composed of 318 amino acids. MT-ND1 is one of seven mitochondrial genes encoding subunits of the enzyme
NADH dehydrogenase (ubiquinone) 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 the ...
, together with
MT-ND2 MT-ND2 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 2 (ND2) protein. The ND2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the fiv ...
,
MT-ND3 MT-ND3 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 3 (ND3) protein. The ND3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the fiv ...
,
MT-ND4 MT-ND4 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4 (ND4) protein. The ND4 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the l ...
,
MT-ND4L MT-ND4L is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4L (ND4L) protein. The ND4L protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is ...
,
MT-ND5 MT-ND5 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 5 protein (ND5). The ND5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the ...
, and
MT-ND6 MT-ND6 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 6 protein (ND6). The ND6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the la ...
. Also known as
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 Electron transport chain, respiratory chains of many organisms from bacteria to ...
, this enzyme is the largest of the respiratory complexes. The structure is L-shaped with a long,
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...
transmembrane A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
domain and a
hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are no ...
domain for the peripheral arm that includes all the known redox centres and the NADH binding site. The MT-ND1 product and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.


Function

MT-ND1-encoded NADH-ubiquinone oxidoreductase chain 1 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 Electron transport chain, respiratory chains of many organisms from bacteria to ...
that is supposed 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 aden ...
dehydrogenation and
electron transfer Electron transfer (ET) occurs when an electron relocates from an atom or molecule to another such chemical entity. ET is a mechanistic description of certain kinds of redox reactions involving transfer of electrons. Electrochemical processes ar ...
to
ubiquinone Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10. It is a 1,4-benzoq ...
(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 aden ...
binds to Complex I and transfers two electrons to the
isoalloxazine ring Flavins (from Latin ''flavus'', "yellow") are organic compounds, like their base, pteridine. They are formed by the tricyclic heterocycle isoalloxazine. The biochemical source is the vitamin riboflavin. The flavin moiety is often attached with ...
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 ...
(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

Pathogenic variants of the mitochondrial gene MT-ND1 are known to cause mtDNA-associated
Leigh syndrome Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fir ...
, as are variants of
MT-ATP6 ''MT-ATP6'' (or ''ATP6'') is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 6' that encodes the ATP synthase Fo subunit 6 (or subunit/chain A). This subunit belongs to the Fo complex of the large, ...
,
MT-TL1 Mitochondrially encoded tRNA leucine 1 (UUA/G) also known as MT-TL1 is a transfer RNA which in humans is encoded by the mitochondrion, mitochondrial ''MT-TL1'' gene. Structure The ''MT-TL1'' gene is located on the Locus (genetics), p arm of the ...
,
MT-TK Mitochondrially encoded tRNA lysine also known as MT-TK is a transfer RNA which in humans is encoded by the mitochondrion, mitochondrial ''MT-TK'' gene. Structure The ''MT-TK'' gene is located on the Locus (genetics), p arm of the mitochondrial ...
,
MT-TW Mitochondrially encoded tRNA tryptophan also known as MT-TW is a transfer RNA which in humans is encoded by the mitochondrial ''MT-TW'' gene. Structure The ''MT-TW'' gene is located on the p arm of the non-nuclear mitochondrial DNA at position ...
, MT-TV,
MT-ND2 MT-ND2 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 2 (ND2) protein. The ND2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the fiv ...
,
MT-ND3 MT-ND3 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 3 (ND3) protein. The ND3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the fiv ...
,
MT-ND4 MT-ND4 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4 (ND4) protein. The ND4 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the l ...
,
MT-ND5 MT-ND5 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 5 protein (ND5). The ND5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the ...
,
MT-ND6 MT-ND6 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 6 protein (ND6). The ND6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the la ...
and
MT-CO3 Cytochrome c oxidase subunit III (COX3) is an enzyme that in humans is encoded by the ''MT-CO3'' gene. It is one of main transmembrane subunits of cytochrome c oxidase. It is also one of the three mitochondrial DNA (mtDNA) encoded subunits ( M ...
. Abnormalities in mitochondrial energy generation result in neurodegenerative disorders like Leigh syndrome, which is characterized by an onset of symptoms between 12 months and three years of age. The symptoms frequently present themselves following a viral infection and include movement disorders and peripheral neuropathy, as well as hypotonia, spasticity and cerebellar ataxia. Roughly half of affected individuals die of respiratory or cardiac failure by the age of three.
Leigh syndrome Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fir ...
is a maternally inherited disorder and its diagnosis is established through genetic testing of the aforementioned mitochondrial genes, including MT-ND1. The m.4171C>A/MT-ND1 mutation also leads to a Leigh-like phenotype as well as bilateral brainstem lesions affecting the vestibular nuclei, resulting in vision loss, vomiting and vertigo. These
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 Electron transport chain, respiratory chains of many organisms from bacteria to ...
genes have been associated with a variety of neurodegenerative disorders, including
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), mitochondrial encephalomyopathy with stroke-like episodes (
MELAS Melas may refer to: * Plural of mela People * Melas (mythology), a number of different characters in Greek mythology * Pavlos Melas (1870–1904), a Hellenic Army officer and a symbol of the Greek Struggle for Macedonia * Chloe Melas, an Ameri ...
), overlap between LHON and MELAS, and the previously mentioned
Leigh syndrome Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fir ...
. Mitochondrial dysfunction resulting from variants of MT-ND1,
MT-ND2 MT-ND2 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 2 (ND2) protein. The ND2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the fiv ...
and
MT-ND4L MT-ND4L is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4L (ND4L) protein. The ND4L protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is ...
have been linked to BMI in adults and implicated in metabolic disorders including obesity, diabetes and hypertension.


References


Further reading

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External links


Mass spectrometry characterization of MT-ND1 at COPaKB
{{Portal bar, Biology, border = no Proteins Human mitochondrial genes