Disease relevance of Tfam

• We have generated an animal model for mitochondrial myopathy by disrupting the gene for mitochondrial transcription factor A (Tfam) in skeletal muscle of the mouse [1].
• Here, we used mice with tissue-specific knockout of mitochondrial transcription factor A (Tfam) that leads to progressive cardiomyopathy [2].

High impact information on Tfam

• The Tfam-mutant mice developed diabetes from the age of approximately 5 weeks and displayed severe mtDNA depletion, deficient oxidative phosphorylation and abnormal appearing mitochondria in islets at the ages of 7-9 weeks [3].
• We have generated a mouse model for mitochondrial diabetes by tissue-specific disruption of the nuclear gene encoding mitochondrial transcription factor A (Tfam, previously mtTFA; ref. 7) in pancreatic beta-cells [3].
• Using a loxP-flanked Tfam allele (TfamloxP) in combination with a cre-recombinase transgene under control of the muscle creatinine kinase promoter, we have disrupted Tfam in heart and muscle [4].
• We found massive apoptosis in Tfam knockout embryos at embryonic day (E) 9.5 and increased apoptosis in the heart of the tissue-specific Tfam knockouts [5].
• The total sarcoplasmic reticulum (SR) Ca(2+) content was decreased in Tfam knockout cells [2].

Biological context of Tfam

• Apoptosis was studied in embryos with homozygous disruption of the mitochondrial transcription factor A gene (Tfam) and tissue-specific Tfam knockout animals with severe respiratory chain deficiency in the heart [5].
• The tissue-specific mitochondrial transcription factor A (Tfam) knockout mice of this study displayed a progressive heart phenotype with depletion of mtDNA and an accompanying severe decline of respiratory chain enzyme activities along with a decreased mitochondrial ATP production rate [6].
• The introduced human TFAM gene was regulated in a similar fashion as the endogenous mouse Tfam gene and expression of the human TFAM protein in the mouse did not result in down-regulation of the endogenous expression [7].
• The gene for the SR Ca(2+) binding protein calsequestrin-2 (CASQ2), as well as other genes encoding proteins involved in SR Ca(2+) handling, showed decreased expression in Tfam knockout hearts [2].
• The comparison with other available Tfam sequences from mammals has revealed a high degree of conservation (above 90%) both in CDS and introns [8].

Anatomical context of Tfam

• Conditional inactivation of the nDNA mitochondrial transcription factor (Tfam) gene in the heart resulted in neonatal lethal cardiomyopathy, while its inactivation in the pancreatic beta-cells caused diabetes [9].
• We have found increased cell death or apoptosis induction in both germ line and tissue-specific Tfam knockouts [10].
• An evolutionary analysis of HMG boxes indicates that the delta HMG boxes are similar to the HMG boxes of tsHMG, a protein that appears in elongating mouse spermatids when they condense and cease transcription, suggesting that delta could play a similar role in the micronucleus [11].
• We also show that the tsHMG protein is the substrate of a Ca2+-phospholipid-dependent protein kinase (protein kinase C) present in testis extracts of adult mice and demonstrate that phosphorylation by protein kinase C is required for both the DNA-binding and the topoisomerase I-dependent supercoiling activities of tsHMG [12].
• To test this possibility, a human cervical carcinoma cell line (HeLa) was constructed which ectopically expressed tsHMG under the control of an inducible promoter [13].

Associations of Tfam with chemical compounds

• In line with this, application of the beta-adrenergic agonist isoproterenol resulted in frequent doublet Ca(2+) transients in Tfam knockout cardiomyocytes [2].
• The binding affinity and specificity of tsHMG for cisplatin-modified DNA are exceptional compared to those of other HMG-domain proteins studied previously [14].

Other interactions of Tfam

• We report here that hallmarks of mtDNA mutation disorders can be reproduced in the mouse using a conditional mutation strategy to manipulate the expression of the gene encoding mitochondrial transcription factor A (Tfam, previously named mtTFA), which regulates transcription and replication of mtDNA [4].

References