Mutations in TFAM, encoding mitochondrial transcription factor A, cause neonatal liver failure associated with mtDNA depletion

Stiles, Ashlee R.; Simon, Mariella; Stover, Alexander E.; Eftekharian, Shaya S.; Khanlou, Négar; Wang, Hanlin L.; Magaki, Shino; Lee, Hane; Partynski, Kate; Dorrani, Nagmeh; Chang, Richard Y.; Martínez‐Agosto, Julian A.; Abdenur, José E.

doi:10.1016/j.ymgme.2016.07.001

Cited by 100 publications

(65 citation statements)

References 39 publications

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“…TFAM A homozygous mutation in TFAM has been found in two siblings with a severe neonatal hepatic syndrome (Stiles et al 2016) and profound mtDNA depletion in liver and skeletal muscle. The mutation (c.533C > T) affects proline 178 (p.Pro178Leu), which is important for the interaction with the mtDNA minor groove.…”

Section: Molecular Geneticsmentioning

confidence: 99%

MtDNA‐maintenance defects: syndromes and genes

Viscomi

Zeviani

2017

J of Inher Metab Disea

152

141

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A large group of mitochondrial disorders, ranging from early-onset pediatric encephalopathic syndromes to late-onset myopathy with chronic progressive external ophthalmoplegia (CPEOs), are inherited as Mendelian disorders characterized by disturbed mitochondrial DNA (mtDNA) maintenance. These errors of nuclear-mitochondrial intergenomic signaling may lead to mtDNA depletion, accumulation of mtDNA multiple deletions, or both, in critical tissues. The genes involved encode proteins belonging to at least three pathways: mtDNA replication and maintenance, nucleotide supply and balance, and mitochondrial dynamics and quality control. In most cases, allelic mutations in these genes may lead to profoundly different phenotypes associated with either mtDNA depletion or multiple deletions.

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Section: Molecular Geneticsmentioning

confidence: 99%

MtDNA‐maintenance defects: syndromes and genes

Viscomi

Zeviani

2017

J of Inher Metab Disea

152

141

View full text Add to dashboard Cite

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“…mtDNA depletion syndromes are characterized by severe declines in mtDNA content in affected tissues and may arise due to defects in genes encoding the mtDNA replication machinery (e.g., POLG , Alpers‐Huttenlocher syndrome) or enzymes required for nucleotide synthesis (e.g., TK2 ). Clinical manifestations of mtDNA depletion syndromes may include myopathy, encephalomyopathy, or neurogastrointestinal or hepatocerebral phenotypes (Stiles et al., ). mtDNA depletion syndromes are typically inherited recessively with an early onset in infancy and early death (Finsterer & Ahting, ).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Human Mitochondrial DNA Content by Southern Blotting and Nonradioactive Probe Hybridization

Wheeler

Young

2019

CP Toxicology

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A single cell can contain several thousand copies of the mitochondrial DNA genome or mtDNA. Tools for assessing mtDNA content are necessary for clinical and toxicological research, as mtDNA depletion is linked to genetic disease and drug toxicity. For instance, mtDNA depletion syndromes are typically fatal childhood disorders that are characterized by severe declines in mtDNA content in affected tissues. Mitochondrial toxicity and mtDNA depletion have also been reported in human immunodeficiency virus–infected patients treated with certain nucleoside reverse transcriptase inhibitors. Further, cell culture studies have demonstrated that exposure to oxidative stress stimulates mtDNA degradation. Here we outline a Southern blot and nonradioactive digoxigenin‐labeled probe hybridization method to estimate mtDNA content in human genomic DNA samples. © 2019 by John Wiley & Sons, Inc.

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“…One such mouse model was created by a cardiac-specific deletion of the main transcription factor for mtDNA (transcription factor A, mitochondrial, Tfam )[6], leading to depletion of electron transport chain (ETC) subunits encoded by mtDNA. In humans, two infants with TFAM mutations died within months of liver failure, had mitochondrial abnormalities on muscle biopsies, and in one case developed clinical heart failure[7]. …”

Section: Introductionmentioning

confidence: 99%

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Sommakia

Houlihan

Deane

et al. 2017

Journal of Molecular and Cellular Cardiology

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Calcium (Ca2+) influx into the mitochondrial matrix stimulates ATP synthesis. Here, we investigate whether mitochondrial Ca2+ transport pathways are altered in the setting of deficient mitochondrial energy synthesis, as increased matrix Ca2+ may provide a stimulatory boost. We focused on mitochondrial cardiomyopathies, which feature such dysfunction of oxidative phosphorylation. We study a mouse model where the main transcription factor for mitochondrial DNA (transcription factor A, mitochondrial, Tfam) has been disrupted selectively in cardiomyocytes. By the second postnatal week (10–15 day old mice), these mice have developed a dilated cardiomyopathy associated with impaired oxidative phosphorylation. We find evidence of increased mitochondrial Ca2+ during this period using imaging, electrophysiology, and biochemistry. The mitochondrial Ca2+ uniporter, the main portal for Ca2+ entry, displays enhanced activity, whereas the mitochondrial sodium-calcium (Na+-Ca2+) exchanger, the main portal for Ca2+ efflux, is inhibited. These changes in activity reflect changes in protein expression of the corresponding transporter subunits. While decreased transcription of Nclx, the gene encoding the Na+-Ca2+ exchanger, explains diminished Na+-Ca2+ exchange, the mechanism for enhanced uniporter expression appears to be post-transcriptional. Notably, such changes allow cardiac mitochondria from Tfam knockout animals to be far more sensitive to Ca2+-induced increases in respiration. In the absence of Ca2+, oxygen consumption declines to less than half of control values in these animals, but rebounds to control levels when incubated with Ca2+. Thus, we demonstrate a phenotype of enhanced mitochondrial Ca2+ in a mitochondrial cardiomyopathy model, and show that such Ca2+ accumulation is capable of rescuing deficits in energy synthesis capacity in vitro.

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Mutations in TFAM, encoding mitochondrial transcription factor A, cause neonatal liver failure associated with mtDNA depletion

Cited by 100 publications

References 39 publications

MtDNA‐maintenance defects: syndromes and genes

MtDNA‐maintenance defects: syndromes and genes

Analysis of Human Mitochondrial DNA Content by Southern Blotting and Nonradioactive Probe Hybridization

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

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