PPRC1, but not PGC-1α, levels directly correlate with expression of mitochondrial proteins in human dermal fibroblasts

Abstract

The XPC protein, which is mutated in xeroderma pigmentosum (XP) complementation group C (XP-C), is a lesion recognition factor in NER, but it has also been shown to interact with and stimulate DNA glycosylases, to act as transcriptional co-activator and on energy metabolism adaptation. We have previously demonstrated that XP-C cells show increased mitochondrial H 2 O 2 production with a shift between respiratory complexes I and II, leading to sensitivity to mitochondrial stress. Here we report a marked decrease in expression of the transcriptional co-activator PGC-1a, a master regulator of mitochondrial biogenesis, in XP-C cells. A transcriptional role for XPC in PGC-1a expression was discarded, as XPC knockdown did not downregulate PGC-1a expression and XPC-corrected cells still showed lower PGC-1a expression. DNA methylation alone did not explain PGC-1a silencing. In four different XP-C cell lines tested, reduction of PGC-1a expression was detected in three, all of them carrying the c.1643_1644delTG mutation (DTG) in XPC. Indeed, all cell lines carrying XPC DTG mutation, whether homozygous or heterozygous, presented decreased PGC-1a expression. However, this alteration in gene expression was not exclusive to XPC DTG cell lines, for other non-related cell lines also showed altered PGC-1a expression. Moreover, PGC1-a expression did not correlate with expression levels of TFAM and SDHA, known PGC-1a target-genes. In turn, PPRC1, another member of the PGC family of transcription co-activators controlling mitochondrial biogenesis, displayed a good correlation between its expression in 10 cell lines and TFAM and SDHA. Nonetheless, PGC-1a knockdown led to a slight decrease of its target-gene protein level, TFAM, and subsequently of a mtDNA-encoded gene, MT-CO2. These results indicate that PGC-1a and PPRC1 cooperate as regulators of mitochondrial biogenesis and maintenance in fibroblasts.

Crosstalk of Oxidative Phosphorylation-Related Subtypes, Establishment of a Prognostic Signature and Immune Infiltration Characteristics in Colorectal Adenocarcinoma

“…The number and time of tumor formation were related to the degree of mtDNA consumption, and long-term depletion leads to the damage of mtDNA replication thus inducing the expression of early development and survival-promoting markers, including sonic hedgehog (SHH) [ 53 ]. PPARG related coactivator 1 (PPRC1), a transcription factor and regulator of mitochondrial biogenesis, may become a new therapeutic target for glioblastoma [ 54 , 55 ]. The above studies clarify the functions of these four genes in oxidative phosphorylation and the roles in tumors.…”

Effect of Ubiquinol on Glaucomatous Neurodegeneration and Oxidative Stress: Studies for Retinal Ganglion Cell Survival and/or Visual Function

“…Because activation of PGC-1α correlates with increased cellular energy demand [ 51 ], it is likely that ubiquinol protects RGCs via maintaining or increasing mtDNA in glaucomatous DBA/2J mice, in turn, leads to the preservation of PGC-1α expression. A previous study demonstrated that PGC-1α expression did not correlate with the expression level of TFAM [ 52 ] even though PGC-1α controls transcriptional expression of TFAM. Therefore, differential expression of PGC-1α and TFAM in glaucomatous retina suggests that ubiquinol may be associated with other transcriptional cofactors.…”