The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms

Abstract

The mitochondrial transcription factor A, or TFAM, is a mitochondrial DNA (mtDNA)‐binding protein essential for genome maintenance. TFAM functions in determining the abundance of the mitochondrial genome by regulating packaging, stability, and replication. More recently, TFAM has been shown to play a central role in the mtDNA stress‐mediated inflammatory response. Emerging evidence indicates that decreased mtDNA copy number is associated with several aging‐related pathologies; however, little is known about the association of TFAM abundance and disease. In this Review, we evaluate the potential associations of altered TFAM levels or mtDNA copy number with neurodegeneration. We also describe potential mechanisms by which mtDNA replication, transcription initiation, and TFAM‐mediated endogenous danger signals may impact mitochondrial homeostasis in Alzheimer, Huntington, Parkinson, and other neurodegenerative diseases.

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…Recent evidence also suggests that mitochondrial dysfunction represents an important cause of the age‐related decline in neurogenesis, as exposure of the SGZ or SVZ to mitogens or enhancement of mitochondrial function restored neurogenesis (Beckervordersandforth et al, ). Notably, the mitochondrial transcription factor A (Tfam), a mitochondrial DNA (mtDNA)‐binding protein essential for genome maintenance, has recently gained attention, as its putative dysfunction may play an important role in neurogenesis defects in the aging hippocampus (Beckervordersandforth et al, ) and aging‐dependent neurodegeneration (Kang, Chu, & Kaufman, ). Tfam has been shown to play a central role in the mtDNA stress‐mediated inflammatory response and recent evidence indicates that decreased mtDNA copy number is associated with several aging‐related pathologies (Kang et al, ).…”

“…Notably, the mitochondrial transcription factor A (Tfam), a mitochondrial DNA (mtDNA)‐binding protein essential for genome maintenance, has recently gained attention, as its putative dysfunction may play an important role in neurogenesis defects in the aging hippocampus (Beckervordersandforth et al, ) and aging‐dependent neurodegeneration (Kang, Chu, & Kaufman, ). Tfam has been shown to play a central role in the mtDNA stress‐mediated inflammatory response and recent evidence indicates that decreased mtDNA copy number is associated with several aging‐related pathologies (Kang et al, ). Of special mention, besides its crucial role for the development, maintenance and protection of midbrain DAergic neurons, the relevance of the transcription factor Nurr1 for adult hippocampal neurogenesis in PD has been recently highlighthed, and several lines of evidence indicate that pharmacological stimulation of Nurr1 can improve behavioral deficits via an increase in hippocampal neurogenesis (Kim et al, ; Kim et al, and section 6.4.1).…”

“…(a) Microscopic brain image at the level of the striatal SVZ. In the inset, a schematic drawing of the four SVZ-cell types: 1. slowly dividing SVZ astrocytes (type B cells), 2. rapidly dividing transitamplifying cells (type C cells, TAPs), 3. migrating neuroblasts (type A cells), and 4. ependymal cells (type E cells) (Doetsch et al, 1997(Doetsch et al, , 1999 several aging-related pathologies (Kang et al, 2018). Of special mention, besides its crucial role for the development, maintenance and protection of midbrain DAergic neurons, the relevance of the transcription factor Nurr1 for adult hippocampal neurogenesis in PD has been recently highlighthed, and several lines of evidence indicate that pharmacological stimulation of Nurr1 can improve behavioral deficits via an increase in hippocampal neurogenesis (Kim et al, 2015;Kim et al, 2016 and section 6.4.1).…”

Systematic review of genetic association studies in people with Lewy body dementia

“…TFAM encodes mitochondrial transcription factor A (TFAM) that is essential for mitochondrial transcription and mtDNA replication. TFAM variants impairing its function may lead to mitochondrial dysfunction and neurodegeneration . TFAM overexpression has been reported to improve hippocampal long‐term potentiation and motor learning memory in mice .…”

“…TFAM overexpression has been reported to improve hippocampal long‐term potentiation and motor learning memory in mice . It has been found to reduce expression of inflammatory mediators such as interleukin‐1β and to reduce mtDNA damage in microglia . Moreover, mitochondrial dysfunction in LBD may lead to a vicious cycle by producing more reactive oxygen species that in turn causing more mitochondrial oxidative damage .…”