Elsevier

Mitochondrion

Volume 25, November 2015, Pages 67-75
Mitochondrion

Review
Regulation of mitochondrial biogenesis through TFAM–mitochondrial DNA interactions: Useful insights from aging and calorie restriction studies

https://doi.org/10.1016/j.mito.2015.10.001Get rights and content

Highlights

  • Mitochondrial biogenesis is regulated also through TFAM–mtDNA interactions.

  • TFAM–mtDNA interactions are modulated by expression, turnover and binding of TFAM.

  • TFAM binding is modulated by post-translational modifications and affinity to mtDNA.

  • TFAM sliding, cooperativity and proteins complexes modulate interactions with mtDNA.

  • Aging and calorie restriction present various modulations of TFAM–mtDNA interactions.

Abstract

Mitochondrial biogenesis is regulated to adapt mitochondrial population to cell energy demands. Mitochondrial transcription factor A (TFAM) performs several functions for mtDNA and interactions between TFAM and mtDNA participate to regulation of mitochondrial biogenesis. Such interactions are modulated through different mechanisms: regulation of TFAM expression and turnover, modulation of TFAM binding activity to mtDNA through post-translational modifications and differential affinity of TFAM, occurrence of TFAM sliding on mtDNA filaments and of cooperative binding among TFAM molecules, modulation of protein–protein interactions. The tissue-specific regulation of mitochondrial biogenesis in aging and calorie restriction (CR) highlights the relevance of modulation of TFAM–mtDNA interactions.

Section snippets

Mitochondrial biogenesis and interactions between mitochondrial transcription factor A and mitochondrial DNA

The very complex process of mitochondrial biogenesis depends on the coordinated expression of nuclear and mitochondrial DNA (mtDNA) and, as a result, it adapts mitochondrial population to cell energy demands. In fact, in response to different physiological and environmental conditions, cell metabolic functions require variable energy amounts, largely provided by mitochondrial oxidative metabolism. Such energy metabolism is usually efficient also due to the constant modulation of mitochondrial

Modulation of TFAM–mtDNA interactions

The overall modulation of TFAM–mtDNA interactions results from various concurrent mechanisms including: a) regulation of TFAM expression and turnover; b) modulation of TFAM binding activity to mtDNA through post-translational modifications of TFAM and differential affinity of TFAM for mtDNA sequences; c) occurrence of TFAM sliding on mtDNA filaments and cooperative binding among TFAM molecules; d) modulation of protein–protein interactions as PGC-1α-TFAM, SIRT1-TFAM and p53-TFAM. According to

TFAM–mtDNA interactions in aged and calorie-restricted animals

Even if TFAM–mtDNA interactions have been deeply studied in vitro, how TFAM regulates mtDNA copy number in vivo is still controversial. TFAM-mediated increase in mtDNA content has been explained by two different mechanisms. According to the first one, transcription-mediated priming of replication should be increased by a higher frequency of TFAM binding at LSP; the second one, instead, proposes that the genome-wide binding of TFAM stabilizes mtDNA content, maybe decreasing DNA turnover. These

Current and future developments

As highlighted above, modulation of TFAM interactions with mtDNA is crucial to regulate mitochondrial biogenesis and adapt it to the always changing cell conditions. Such modulation can be obtained likely through multiple mechanisms among which alteration of the binding activity of TFAM to mtDNA and regulation of TFAM expression appear relevant (Fig. 4).

PGC-1 coactivators are master regulators of mitochondrial biogenesis, obtained through the coordinated expression of mitochondrial proteins

Conflict of interest

The authors have no actual or potential conflict of interest associated with this research.

Acknowledgments

This research was supported by grant to AMSL (Contributo di Ateneo Bari 2012). We thank Flavio Fracasso, MS, for assisting with the figures.

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