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

Author(s)

Mori, Mateus Prates ; de Souza-Pinto, Nadja Cristhina

• Document type: Journal article
• Source: GENETICS AND MOLECULAR BIOLOGY; v. 43, p. 10-pg., 2020-01-01.

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 H2O2 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-1 alpha, a master regulator of mitochondrial biogenesis, in XP-C cells. A transcriptional role for XPC in PGC-1 alpha expression was discarded, as XPC knockdown did not downregulate PGC-1 alpha expression and XPC-corrected cells still showed lower PGC-1 alpha expression. DNA methylation alone did not explain PGC-1 alpha silencing. In four different XP-C cell lines tested, reduction of PGC-1 alpha expression was detected in three, all of them carrying the c.1643_1644deITG mutation (Delta TG) in XPC. Indeed, all cell lines carrying XPC Delta TG mutation, whether homozygous or heterozygous, presented decreased PGC-1 alpha expression. However, this alteration in gene expression was not exclusive to XPC Delta TG cell lines, for other non-related cell lines also showed altered PGC-1 alpha expression. Moreover, PGC-1 alpha expression did not correlate with expression levels of TFAM and SDHA, known PGC-1 alpha 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-1 alpha 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-1 alpha and PPRC1 cooperate as regulators of mitochondrial biogenesis and maintenance in fibroblasts. (AU)

• FAPESP's process: 16/15407-7 - Investigating the role of the TG mutation in XPC gene on expression of the transcriptional co-activator PGC-1a
• Grantee: Mateus Prates Mori
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 10/51906-1 - Mitochondrial bioenergetics, ion transport, redox state and DNA metabolism
• Grantee: Alicia Juliana Kowaltowski
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/04372-0 - Mitochondrial DNA: mechanisms for genome integrity maintenance and impact on disease
• Grantee: Nadja Cristhina de Souza Pinto
• Support Opportunities: Research Projects - Thematic Grants