Tetramethylpyrazine blocks TFAM degradation and up-regulates mitochondrial DNA copy number by interacting with TFAM

Abstract

The natural small molecule compound: 2,3,5,6-tetramethylpyrazine (TMP), is a major component of the Chinese medicine Chuanxiong, which has wide clinical applications in dilating blood vessels, inhibiting platelet aggregation and treating thrombosis. Recent work suggests that TMP is also an antitumour agent. Despite its chemotherapeutic potential, the mechanism(s) underlying TMP action are unknown. Herein, we demonstrate that TMP binds to mitochondrial transcription factor A (TFAM) and blocks its degradation by the mitochondrial Lon protease. TFAM is a key regulator of mtDNA replication, transcription and transmission. Our previous work showed that when TFAM is not bound to DNA, it is rapidly degraded by the ATP-dependent Lon protease, which is essential for mitochondrial proteostasis. In cultured cells, TMP specifically blocks Lon-mediated degradation of TFAM, leading to TFAM accumulation and subsequent up-regulation of mtDNA content in cells with substantially low levels of mtDNA. In vitro protease assays show that TMP does not directly inhibit mitochondrial Lon, rather interacts with TFAM and blocks degradation. Pull-down assays show that biotinylated TMP interacts with TFAM. These findings suggest a novel mechanism whereby TMP stabilizes TFAM and confers resistance to Lon-mediated degradation, thereby promoting mtDNA up-regulation in cells with low mtDNA content.

Effects of eicosapentaenoic acid and docosahexaenoic acid on C2C12 cell adipogenesis and inhibition of myotube formation

“…It has been shown that mitochondrial function and subsequent cell growth and morphology can be compromised by TFAM gene knockdown, followed by reducing mtDNA copy number and expression (Jeng et al 2008). Consistent with previous studies, impaired TFAM expression negatively affected the mtDNA/nDNA (mitochondrial DNA per nuclear DNA copy number) ratio and mitochondrial respiratory chain efficiency (Wang et al 2001; Woo et al 2012; Xie et al 2016; Lan et al 2017). Decreased mitochondrial biosynthesis was shown by the mtDNA/nDNA ratio (Phillips et al 2014; Hsueh et al 2018).…”

TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis

“…For example, the experimental drug LY379268 was reported to upregulate the expression of TFAM and prevent diabetic peripheral neuropathy by improving mitochondrial function in dorsal root ganglion neurons (Chandrasekaran et al, 2017). In addition, etramethylpyrazine, a natural small molecule compound, was found to stabilize TFAM by directly interacting with TFAM, which blocked Lon protease access and thus decreased TFAM degradation (Lan et al, 2017). This metastasis-promoting effect of TFAM loss was strongly supported by both RNA-Seq and ATAC-seq, which showed that GO terms such as ECM remodeling, angiogenesis, cell migration, and adhesion were enriched.…”

Melatonin reduces intramuscular fat deposition by promoting lipolysis and increasing mitochondrial function

“…Melatonin may be closely related to the PKA and ERK1/2 pathways (38)(39)(40), which play a key role in lipolysis (41). Melatonin can trigger PKA activation in the rodent malaria parasite, Plasmodium chabaudi (42).…”

“…This is the main route of fatty acid degradation and is closely linked to mitochondrial content and respiration capability (48). A previous study showed that an increase of PGC-1 promotes the expression of TFAM, an important regulator in mitochondrial biogenesis (40). TFAM translocates into the mitochondria to stimulate DNA replication and gene expression (49,50), thereby promoting mitochondrial biogenesis and function.…”