Investigation of possible changes in mitochondrial morphology and mitophagy levels in xeroderma pigmentosum variant cell lines

• Grant number: 25/00371-6
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: August 04, 2025
• End date: February 03, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Nadja Cristhina de Souza Pinto
• Grantee: Beatriz Kopel
• Supervisor: Tinna Stevnsner
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Aarhus University, Denmark
• Associated to the scholarship: 24/03685-9 - Characterization of mitochondrial function in cells from patients with Xeroderma pigmentosum variant to investigate a possible link between DNA damage response and energetic metabolism, BP.MS

Abstract

Xeroderma pigmentosum (XP) is a rare autosomal disease in which patients present photosensitivity, high incidence of melanoma and non-melanocytic skin tumors, among other symptoms. XP is caused by mutations 7 genes which encode components of the nucleotide excision repair pathway, or mutations in the POLH gene that codes for the translesion synthesis DNA polymerase eta (DNA pol eta), giving rise to XP variant (XP-V). DNA pol eta bypasses cyclobutane pyrimidine dimers in an error-free manner, among other lesions with varying fidelity. Our previous results show that XP-V cells accumulate superoxide anions after UVA irradiation and mutations with an oxidative DNA damage signature even under basal conditions suggest that XP-V cells are under a basal redox imbalance condition. We also have preliminary data showing decreased GSH/GSSG ratio in XP-V cells, as well as altered expression of antioxidant enzymes. Together, these results raised the possibility that redox imbalance might contribute to genomic instability and carcinogenesis in XP-V patients. In this context, we are now investigating whether XP-V cells have impaired mitochondrial function, which could be the cause or contribute to the redox imbalance observed. We found that XP-V cells display lower basal, ATP-linked and maximum mitochondrial respiration, and lower ATP levels than a complemented isogenic control. To further evaluate mitochondrial integrity in XP-V cells, we propose to determine whether mitophagy levels and mitochondrial morphology are affected in XP-V cells, to gain further insight into the mechanistic link between mitochondrial dysfunction and the XP pathology. (AU)