Identification of ataxia‐associated mtDNA mutations (m.4052T>C and m.9035T>C) and evaluation of their pathogenicity in transmitochondrial cybrids
Identifieur interne : 001F92 ( Main/Exploration ); précédent : 001F91; suivant : 001F93Identification of ataxia‐associated mtDNA mutations (m.4052T>C and m.9035T>C) and evaluation of their pathogenicity in transmitochondrial cybrids
Auteurs : Marianna Sikorska [Canada] ; Jagdeep K. Sandhu [Canada] ; David K. Simon [États-Unis] ; Vimukthi Pathiraja [États-Unis] ; Caroline Sodja [Canada] ; Yan Li [Canada] ; Maria Ribecco-Lutkiewicz [Canada] ; Patricia Lanthier [Canada] ; Henryk Borowy-Borowski [Canada] ; Adrian Upton [Canada] ; Sandeep Raha [Canada] ; Stefan M. Pulst [États-Unis] ; Mark A. Tarnopolsky [Canada]Source :
- Muscle & Nerve [ 0148-639X ] ; 2009-09.
English descriptors
Abstract
The potential pathogenicity of two homoplasmic mtDNA point mutations, 9035T>C and 4452T>C, found in a family afflicted with maternally transmitted cognitive developmental delay, learning disability, and progressive ataxia was evaluated using transmitochondrial cybrids. We confirmed that the 4452T>C transition in tRNAMet represented a polymorphism; however, 9035T>C conversion in the ATP6 gene was responsible for a defective F0‐ATPase. Accordingly, mutant cybrids had a reduced oligomycin‐sensitive ATP hydrolyzing activity. They had less than half of the steady‐state content of ATP and nearly an 8‐fold higher basal level of reactive oxygen species (ROS). Mutant cybrids were unable to cope with additional insults, i.e., glucose deprivation or tertiary‐butyl hydroperoxide, and they succumbed to either apoptotic or necrotic cell death. Both of these outcomes were prevented by the antioxidants CoQ10 and vitamin E, suggesting that the abnormally high levels of ROS were the triggers of cell death. In conclusion, the principal metabolic defects, i.e., energy deficiency and ROS burden, resulted from the 9035T>C mutation and could be responsible for the development of clinical symptoms in this family. Furthermore, antioxidant therapy might prove helpful in the management of this disease. Muscle Nerve, 2009
Url:
DOI: 10.1002/mus.21355
Affiliations:
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Tarnopolsky, Department of Medicine (Neurology), McMaster University, Hamilton, Ontario</wicri:regionArea><orgName type="university">Université McMaster</orgName><placeName><settlement type="city">Hamilton (Ontario)</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Sandhu, Jagdeep K" sort="Sandhu, Jagdeep K" uniqKey="Sandhu J" first="Jagdeep K." last="Sandhu">Jagdeep K. Sandhu</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Neurogenesis and Brain Repair Group M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, K1A 0R6</wicri:regionArea><wicri:noRegion>K1A 0R6</wicri:noRegion></affiliation></author><author><name sortKey="Simon, David K" sort="Simon, David K" uniqKey="Simon D" first="David K." last="Simon">David K. Simon</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Pathiraja, Vimukthi" sort="Pathiraja, Vimukthi" uniqKey="Pathiraja V" first="Vimukthi" last="Pathiraja">Vimukthi Pathiraja</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Sodja, Caroline" sort="Sodja, Caroline" uniqKey="Sodja C" first="Caroline" last="Sodja">Caroline Sodja</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Neurogenesis and Brain Repair Group M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, K1A 0R6</wicri:regionArea><wicri:noRegion>K1A 0R6</wicri:noRegion></affiliation></author><author><name sortKey="Li, Yan" sort="Li, Yan" uniqKey="Li Y" first="Yan" last="Li">Yan Li</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Neurogenesis and Brain Repair Group M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, K1A 0R6</wicri:regionArea><wicri:noRegion>K1A 0R6</wicri:noRegion></affiliation></author><author><name sortKey="Ribecco Utkiewicz, Maria" sort="Ribecco Utkiewicz, Maria" uniqKey="Ribecco Utkiewicz M" first="Maria" last="Ribecco-Lutkiewicz">Maria Ribecco-Lutkiewicz</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Neurogenesis and Brain Repair Group M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, K1A 0R6</wicri:regionArea><wicri:noRegion>K1A 0R6</wicri:noRegion></affiliation></author><author><name sortKey="Lanthier, Patricia" sort="Lanthier, Patricia" uniqKey="Lanthier P" first="Patricia" last="Lanthier">Patricia Lanthier</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Neurogenesis and Brain Repair Group M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, K1A 0R6</wicri:regionArea><wicri:noRegion>K1A 0R6</wicri:noRegion></affiliation></author><author><name sortKey="Borowy Orowski, Henryk" sort="Borowy Orowski, Henryk" uniqKey="Borowy Orowski H" first="Henryk" last="Borowy-Borowski">Henryk Borowy-Borowski</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Neurogenesis and Brain Repair Group M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, K1A 0R6</wicri:regionArea><wicri:noRegion>K1A 0R6</wicri:noRegion></affiliation></author><author><name sortKey="Upton, Adrian" sort="Upton, Adrian" uniqKey="Upton A" first="Adrian" last="Upton">Adrian Upton</name><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine (Neurology), McMaster University, Hamilton, Ontario</wicri:regionArea><orgName type="university">Université McMaster</orgName><placeName><settlement type="city">Hamilton (Ontario)</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Raha, Sandeep" sort="Raha, Sandeep" uniqKey="Raha S" first="Sandeep" last="Raha">Sandeep Raha</name><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pediatrics (Neuromuscular and Neurometabolic Disorders), 1200 Main Street West, Room 2U26, McMaster University, Hamilton, Ontario, L8N 3Z5</wicri:regionArea><orgName type="university">Université McMaster</orgName><placeName><settlement type="city">Hamilton (Ontario)</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Pulst, Stefan M" sort="Pulst, Stefan M" uniqKey="Pulst S" first="Stefan M." last="Pulst">Stefan M. Pulst</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Cedars‐Sinai Medical Center, Los Angeles, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Tarnopolsky, Mark A" sort="Tarnopolsky, Mark A" uniqKey="Tarnopolsky M" first="Mark A." last="Tarnopolsky">Mark A. Tarnopolsky</name><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine (Neurology), McMaster University, Hamilton, Ontario</wicri:regionArea><orgName type="university">Université McMaster</orgName><placeName><settlement type="city">Hamilton (Ontario)</settlement><region type="state">Ontario</region></placeName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pediatrics (Neuromuscular and Neurometabolic Disorders), 1200 Main Street West, Room 2U26, McMaster University, Hamilton, Ontario, L8N 3Z5</wicri:regionArea><orgName type="university">Université McMaster</orgName><placeName><settlement type="city">Hamilton (Ontario)</settlement><region type="state">Ontario</region></placeName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Marianna Sikorska, Neurogenesis and Brain Repair Group M54, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, K1A 0R6, CanadaMark A. Tarnopolsky, Department of Medicine (Neurology), McMaster University, Hamilton, Ontario</wicri:regionArea><orgName type="university">Université McMaster</orgName><placeName><settlement type="city">Hamilton (Ontario)</settlement><region type="state">Ontario</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Muscle & Nerve</title><title level="j" type="sub">Official Journal of the American Association of Electrodiagnostic Medicine</title><title level="j" type="abbrev">Muscle Nerve</title><idno type="ISSN">0148-639X</idno><idno type="eISSN">1097-4598</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-09">2009-09</date><biblScope unit="volume">40</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="381">381</biblScope><biblScope unit="page" to="394">394</biblScope></imprint><idno type="ISSN">0148-639X</idno></series><idno type="istex">97C80F254A6FE345D9DBA838463CB6A4DC928E70</idno><idno type="DOI">10.1002/mus.21355</idno><idno type="ArticleID">MUS21355</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0148-639X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>antioxidant</term><term>homoplasmic mutations</term><term>mitochondrial</term><term>oxidative stress</term><term>therapy</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The potential pathogenicity of two homoplasmic mtDNA point mutations, 9035T>C and 4452T>C, found in a family afflicted with maternally transmitted cognitive developmental delay, learning disability, and progressive ataxia was evaluated using transmitochondrial cybrids. We confirmed that the 4452T>C transition in tRNAMet represented a polymorphism; however, 9035T>C conversion in the ATP6 gene was responsible for a defective F0‐ATPase. Accordingly, mutant cybrids had a reduced oligomycin‐sensitive ATP hydrolyzing activity. They had less than half of the steady‐state content of ATP and nearly an 8‐fold higher basal level of reactive oxygen species (ROS). Mutant cybrids were unable to cope with additional insults, i.e., glucose deprivation or tertiary‐butyl hydroperoxide, and they succumbed to either apoptotic or necrotic cell death. Both of these outcomes were prevented by the antioxidants CoQ10 and vitamin E, suggesting that the abnormally high levels of ROS were the triggers of cell death. In conclusion, the principal metabolic defects, i.e., energy deficiency and ROS burden, resulted from the 9035T>C mutation and could be responsible for the development of clinical symptoms in this family. Furthermore, antioxidant therapy might prove helpful in the management of this disease. Muscle Nerve, 2009</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Californie</li><li>Massachusetts</li><li>Ontario</li></region><settlement><li>Hamilton (Ontario)</li></settlement><orgName><li>Université McMaster</li></orgName></list><tree><country name="Canada"><noRegion><name sortKey="Sikorska, Marianna" sort="Sikorska, Marianna" uniqKey="Sikorska M" first="Marianna" last="Sikorska">Marianna Sikorska</name></noRegion><name sortKey="Borowy Orowski, Henryk" sort="Borowy Orowski, Henryk" uniqKey="Borowy Orowski H" first="Henryk" last="Borowy-Borowski">Henryk Borowy-Borowski</name><name sortKey="Lanthier, Patricia" sort="Lanthier, Patricia" uniqKey="Lanthier P" first="Patricia" last="Lanthier">Patricia Lanthier</name><name sortKey="Li, Yan" sort="Li, Yan" uniqKey="Li Y" first="Yan" last="Li">Yan Li</name><name sortKey="Raha, Sandeep" sort="Raha, Sandeep" uniqKey="Raha S" first="Sandeep" last="Raha">Sandeep Raha</name><name sortKey="Ribecco Utkiewicz, Maria" sort="Ribecco Utkiewicz, Maria" uniqKey="Ribecco Utkiewicz M" first="Maria" last="Ribecco-Lutkiewicz">Maria Ribecco-Lutkiewicz</name><name sortKey="Sandhu, Jagdeep K" sort="Sandhu, Jagdeep K" uniqKey="Sandhu J" first="Jagdeep K." last="Sandhu">Jagdeep K. Sandhu</name><name sortKey="Sikorska, Marianna" sort="Sikorska, Marianna" uniqKey="Sikorska M" first="Marianna" last="Sikorska">Marianna Sikorska</name><name sortKey="Sodja, Caroline" sort="Sodja, Caroline" uniqKey="Sodja C" first="Caroline" last="Sodja">Caroline Sodja</name><name sortKey="Tarnopolsky, Mark A" sort="Tarnopolsky, Mark A" uniqKey="Tarnopolsky M" first="Mark A." last="Tarnopolsky">Mark A. Tarnopolsky</name><name sortKey="Tarnopolsky, Mark A" sort="Tarnopolsky, Mark A" uniqKey="Tarnopolsky M" first="Mark A." last="Tarnopolsky">Mark A. Tarnopolsky</name><name sortKey="Tarnopolsky, Mark A" sort="Tarnopolsky, Mark A" uniqKey="Tarnopolsky M" first="Mark A." last="Tarnopolsky">Mark A. Tarnopolsky</name><name sortKey="Upton, Adrian" sort="Upton, Adrian" uniqKey="Upton A" first="Adrian" last="Upton">Adrian Upton</name></country><country name="États-Unis"><region name="Massachusetts"><name sortKey="Simon, David K" sort="Simon, David K" uniqKey="Simon D" first="David K." last="Simon">David K. Simon</name></region><name sortKey="Pathiraja, Vimukthi" sort="Pathiraja, Vimukthi" uniqKey="Pathiraja V" first="Vimukthi" last="Pathiraja">Vimukthi Pathiraja</name><name sortKey="Pulst, Stefan M" sort="Pulst, Stefan M" uniqKey="Pulst S" first="Stefan M." last="Pulst">Stefan M. Pulst</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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