Which of the following cellular deficiencies would most likely be related to these mt-nd1 mutations?

mitochondrially encoded NADH dehydrogenase 1

Normal Function

The MT-ND1 gene provides instructions for making a protein called NADH dehydrogenase 1. This protein is part of a large enzyme complex known as complex I, which is active in mitochondria. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. These cellular structures produce energy through a process called oxidative phosphorylation, which uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell's main energy source.

Complex I is one of several enzyme complexes necessary for oxidative phosphorylation. Within mitochondria, these complexes are embedded in a tightly folded, specialized membrane called the inner mitochondrial membrane. During oxidative phosphorylation, mitochondrial enzyme complexes carry out chemical reactions that drive the production of ATP. Specifically, they create an unequal electrical charge on either side of the inner mitochondrial membrane through a step-by-step transfer of negatively charged particles called electrons. This difference in electrical charge provides the energy for ATP production.

Complex I is responsible for the first step in the electron transport process, the transfer of electrons from a molecule called NADH to another molecule called ubiquinone. Electrons are then passed from ubiquinone through several other enzyme complexes to provide energy for the generation of ATP.

Health Conditions Related to Genetic Changes

Leber hereditary optic neuropathy

Several mutations in the MT-ND1 gene are known to cause Leber hereditary optic neuropathy. Each of these mutations changes a single DNA building block (nucleotide) in the gene. One common MT-ND1 mutation is responsible for about 13 percent of all cases of Leber hereditary optic neuropathy. This mutation replaces the nucleotide guanine with the nucleotide adenine at gene position 3460 (written as G3460A). This change is associated with moderately severe cases of Leber hereditary optic neuropathy; however, 20 percent to 40 percent of people with vision loss due to this mutation experience some recovery of vision.

Researchers are investigating how mutations in the MT-ND1 gene lead to Leber hereditary optic neuropathy. These genetic changes appear to disrupt the normal activity of complex I in the mitochondrial inner membrane, which may affect the generation of ATP. MT-ND1 mutations also may increase the production within mitochondria of potentially harmful molecules called reactive oxygen species. It remains unclear, however, why the effects of these mutations are often limited to the nerve that relays visual information from the eye to the brain (the optic nerve). Additional genetic and environmental factors probably contribute to the vision loss and other medical problems associated with Leber hereditary optic neuropathy.

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Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

MT-ND1 mutations are a rare cause of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Most cases of MELAS are caused by mutations in other mitochondrial genes, but a small number of cases resulting from mutations in the MT-ND1 gene have been reported. Fewer than five mutations, each of which alters a single DNA building block (nucleotide) in the gene, have been identified in affected individuals. These genetic changes reduce the activity of complex I, which disrupts energy production within mitochondria. Although these abnormalities have the greatest impact on tissues that require a lot of energy (such as the brain and muscles), researchers have not determined how changes in the MT-ND1 gene lead to the specific signs and symptoms of MELAS.

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Leigh syndrome

MedlinePlus Genetics provides information about Leigh syndrome

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Mitochondrial complex I deficiency

MedlinePlus Genetics provides information about Mitochondrial complex I deficiency

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Other disorders

A mutation in the MT-ND1 gene has been reported in a few cases of adult-onset dystonia. Dystonia is a movement disorder that involves involuntary tensing of the muscles (muscle contractions), tremors, and other uncontrolled movements. The MT-ND1 mutation associated with these rare cases replaces the nucleotide adenine with the nucleotide guanine at gene position 3796 (written as A3796G). Further studies are needed to determine whether this genetic change combines with other genetic and environmental factors to increase the risk of developing adult-onset dystonia.

Other Names for This Gene

References

• Baracca A, Solaini G, Sgarbi G, Lenaz G, Baruzzi A, Schapira AH, Martinuzzi A, Carelli V. Severe impairment of complex I-driven adenosine triphosphate synthesis in leber hereditary optic neuropathy cybrids. Arch Neurol. 2005 May;62(5):730-6. Citation on PubMed
• Cock HR, Cooper JM, Schapira AH. Functional consequences of the 3460-bp mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. J Neurol Sci. 1999 May 1;165(1):10-7. Citation on PubMed
• Huoponen K. Leber hereditary optic neuropathy: clinical and molecular genetic findings. Neurogenetics. 2001 Jul;3(3):119-25. Review. Citation on PubMed
• Kervinen M, Hinttala R, Helander HM, Kurki S, Uusimaa J, Finel M, Majamaa K, Hassinen IE. The MELAS mutations 3946 and 3949 perturb the critical structure in a conserved loop of the ND1 subunit of mitochondrial complex I. Hum Mol Genet. 2006 Sep 1;15(17):2543-52. Epub 2006 Jul 18. Citation on PubMed
• Kirby DM, McFarland R, Ohtake A, Dunning C, Ryan MT, Wilson C, Ketteridge D, Turnbull DM, Thorburn DR, Taylor RW. Mutations of the mitochondrial ND1 gene as a cause of MELAS. J Med Genet. 2004 Oct;41(10):784-9. Citation on PubMed or Free article on PubMed Central
• Lenaz G, Baracca A, Carelli V, D'Aurelio M, Sgarbi G, Solaini G. Bioenergetics of mitochondrial diseases associated with mtDNA mutations. Biochim Biophys Acta. 2004 Jul 23;1658(1-2):89-94. Review. Citation on PubMed
• Mitchell AL, Elson JL, Howell N, Taylor RW, Turnbull DM. Sequence variation in mitochondrial complex I genes: mutation or polymorphism? J Med Genet. 2006 Feb;43(2):175-9. Epub 2005 Jun 21. Citation on PubMed or Free article on PubMed Central
• Simon DK, Friedman J, Breakefield XO, Jankovic J, Brin MF, Provias J, Bressman SB, Charness ME, Tarsy D, Johns DR, Tarnopolsky MA. A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia. Neurogenetics. 2003 Aug;4(4):199-205. Epub 2003 May 17. Citation on PubMed
• Valentino ML, Barboni P, Ghelli A, Bucchi L, Rengo C, Achilli A, Torroni A, Lugaresi A, Lodi R, Barbiroli B, Dotti M, Federico A, Baruzzi A, Carelli V. The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy. Ann Neurol. 2004 Nov;56(5):631-41. Citation on PubMed

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