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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: GENETICS AND MOLECULAR BIOLOGY; v. 43, p. 10-pg., 2020-01-01.

Resumo

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)

• Processo FAPESP: 16/15407-7 - Investigação do papel da mutação TG no gene XPC na expressão do coativador transcricional PGC-1a
• Beneficiário: Mateus Prates Mori
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 10/51906-1 - Bioenergética, transporte iônico, balanço redox e metabolismo de DNA em mitocôndrias
• Beneficiário: Alicia Juliana Kowaltowski
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/04372-0 - DNA mitocondrial: mecanismos de manutenção de sua estabilidade e impacto em doenças
• Beneficiário: Nadja Cristhina de Souza Pinto
• Modalidade de apoio: Auxílio à Pesquisa - Temático