Association study of two genetic variants in mitochondrial transcription factor A (TFAM) in Alzheimer's and Parkinson's disease

Belin, Andrea Carmine; Björk, Behnosh F.; Westerlund, Marie; Galter, Dagmar; Sydow, Olof; Lind, Charlotta; Pernold, Karin; Rosvall, Lina; Håkansson, Anna; Winblad, Bengt; Nissbrandt, Hans; Graff, Caroline; Olson, Lar̀s

doi:10.1016/j.neulet.2007.05.010

Cited by 39 publications

(24 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, TFAM transgenic mice are protected from age-dependent memory impairment and mitochondrial DNA damage in brain microglia (Hayashi et al, 2008). Of note, a TFAM genetic variant has been associated with Alzheimer’s disease in several populations (Belin et al, 2007; Bertram et al, 2007). The published results together with our findings strongly implicate TFAM in the preservation of mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

“…Organ-targeted depletion of TFAM has substantiated the importance of mitochondrial metabolism in various cell types, including cardiomyocytes and β-cells (Larsson and Rustin, 2001; Silva et al, 2000). Furthermore, mitochondrial dysfunction accelerates biological aging and a polymorphism in the tfam gene has been associated with familial Alzheimer’s disease (Belin et al, 2007). Conversely, mice overexpressing TFAM are protected from age-dependent impairment of brain performance by preserving mitochondrial function in microglia (Hayashi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PDX1 Deficiency Causes Mitochondrial Dysfunction and Defective Insulin Secretion through TFAM Suppression

et al. 2009

View full text Add to dashboard Cite

Mutations in the transcription factor Pdx1 cause maturity-onset diabetes of the young 4 (MODY4). Islet transduction with dominant negative Pdx1 (RIPDN79PDX1) impairs mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). Transcript profiling revealed suppression of nuclear encoded mitochondrial factor A (TFAM). Herein, we show that Pdx1 suppression in adult mice reduces islet TFAM expression coinciding with hyperglycaemia. We define TFAM as a direct target of Pdx1 both in rat INS1 cells and human islets. Adenoviral overexpression of TFAM along with RIPDN79PDX1 in isolated rat islets rescued mitochondrial DNA (mtDNA) copy number and restored respiratory chain activity as well as glucose-induced ATP synthesis and insulin secretion. CGP37157, which blocks the mitochondrial Na+/Ca2+ exchanger, restored ATP generation and GSIS in RIPDN79PDX1 islets, thereby bypassing the transcriptional defect. Thus, the genetic control by the β-cell specific factor Pdx1 of the ubiquitous gene TFAM maintains β-cell mtDNA vital for ATP production and normal GSIS.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PDX1 Deficiency Causes Mitochondrial Dysfunction and Defective Insulin Secretion through TFAM Suppression

et al. 2009

View full text Add to dashboard Cite

show abstract

“…To date, there are no confirmed TFAM clinical mutations, although the genetic variant rs2306604 may be linked to Alzheimer’s disease (Belin et al, 2007) pending more comprehensive clinical and biochemical analyses. However, TFAM has shown promise for being an anti-aging therapeutic agent.…”

Section: Age-related Mitochondrial Diseases Associated With Defectmentioning

confidence: 99%

Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases

DeBalsi

Hoff

Copeland

2017

Ageing Research Reviews

154

124

View full text Add to dashboard Cite

As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases. Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery. Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations. Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration. We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases. Additionally, interventions to improve mitochondrial function and attenuate the symptoms of aging are examined.

show abstract

“…Recent studies suggest particular TOMM40 polymorphisms may affect the age of AD onset more stringently than APOE polymorphisms, leading some to speculate this mitochondrial protein is potentially more relevant to AD than apolipoprotein E (223). Several studies have also associated variation in the TFAM gene with AD risk (5,14,102,303). The TFAM gene encodes transcription factor A of the mitochondria, which plays a major role in mtDNA replication and expression (50, 82,134,200).…”

Section: Synthesizing the Data: The Mitochondrial Cascade Hypothesismentioning

confidence: 99%

Mitochondria and Cell Bioenergetics: Increasingly Recognized Components and a Possible Etiologic Cause of Alzheimer's Disease

Swerdlow

2012

Antioxidants & Redox Signaling

180

186

View full text Add to dashboard Cite

show abstract

Association study of two genetic variants in mitochondrial transcription factor A (TFAM) in Alzheimer's and Parkinson's disease

Cited by 39 publications

References 45 publications

PDX1 Deficiency Causes Mitochondrial Dysfunction and Defective Insulin Secretion through TFAM Suppression

PDX1 Deficiency Causes Mitochondrial Dysfunction and Defective Insulin Secretion through TFAM Suppression

Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases

Mitochondria and Cell Bioenergetics: Increasingly Recognized Components and a Possible Etiologic Cause of Alzheimer's Disease

Contact Info

Product

Resources

About