New Roles of Mitochondrial Transcription Factor A in Cancer

Yoichiro Yoshida,Seiichiro Hoshino,

doi:10.4172/2161-0398.1000101

Abstract

Mitochondria are the main sites of energy production in almost all eukaryotic cells. Mitochondria use oxidative phosphorylation to convert redox energy of substrates into adenosine triphosphate (ATP). Mitochondrial transcription factor A (mtTFA; also known as TFAM) is necessary for both transcription and maintenance of mitochondrial DNA (mtDNA), and it is one of the high mobility group (HMG) proteins that preferentially recognizes cisplatin-damaged DNA and oxidized DNA. Loss of mtTFA causes depletion of mtDNA, loss of mitochondrial transcripts, loss of mtDNA-encoded polypeptides, and severe respiratory chain deficiency. Mitochondria play a critical role in cancer cell metabolism and are also essential for cell proliferation. It is well known that mitochondrial uncoupling mediates the metabolic shift to aerobic glycolysis in cancer cells. Thus, mitochondria control cell survival and growth. In addition, the number of mitochondria correlates with the growth rate of cancer cells. The information gleaned from this review may provide critical clues to novel therapeutic interventions aimed at overcoming cancer. More detailed functional analyses of mtTFA should further elucidate its role in mitochondrial genome instability and apoptosis.c

Highlights

Mitochondria generate cellular energy in the form of adenosine triphosphate (ATP) by the process of oxidative phosphorylation
We reported the relationship between Mitochondrial transcription factor A (mtTFA) expression and clinicopathological variables in endometrial carcinomas [83]. mtTFA mutations induce mitochondrial DNA (mtDNA) depletion and result in decreased tumor sensitivity to cisplatin in most colorectal cancer (CRC) with microsatellite instability (MSI) [84]
The presence of these alterations suggests the potential importance of mtTFA in tumorigenesis of CRC with MSI and implicates mtTFAdependent mitochondrial instability as the unique pathogenetic factor for CRC with MSI. mtTFA mutation may be potentially useful in predicting outcomes and selecting chemotherapy for patients with microsatellite-unstable CRC

Summary

Introduction

Mitochondria generate cellular energy in the form of adenosine triphosphate (ATP) by the process of oxidative phosphorylation. Otto Warburg observed that tumor slices have elevated levels of glucose consumption and lactate production in the presence of ample oxygen (termed the Warburg effect) [3] He later postulated that cancer originates from irreversible injury to respiration followed by an increase in glycolysis to replace ATP loss due to defective oxidative phosphorylation [4]. Structure of mtTFA mtTFA, which is a nucleus-encoded DNA binding protein of 246 amino acids, is a member of high mobility group (HMG) proteins and contains 2 HMG-box domains. HMG proteins are able to recognize structurally altered DNA Both HMG1 and HMG2 could not bind to oxidized DNA indicating that mtTFA is functionally different from nuclear HMG proteins, HMG1 and HMG2. The homology between mtTFA and other nuclear HMG proteins show low homology It is unclear which amino acid sequence may involve generating the oxidized DNA recognition activity of mtTFA. The oxidative phosphorylation system consists of 5 multi-subunit enzymatic complexes formed from the gene products of approximately 74 nuclear genes and the 13 mitochondrial genes [11,44] (Table 1)

Cytochrome b

Recognition of Damaged DNA

Summary and Future Perspectives