Mitochondrial DNA methylation impacts The P53/Pgc1-alpha/Nrf1 axis in a redox imbalance context

• Grant number: 22/02482-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: April 01, 2023
• Status: Discontinued
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Nadja Cristhina de Souza Pinto
• Grantee: Laís Yoshie Morikawa Muta
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/04372-0 - Mitochondrial DNA: mechanisms for genome integrity maintenance and impact on disease, AP.TEM
• Associated scholarship(s): 24/07355-3 - Mitochondrial methylation profile in response to redox imbalance and alteration in p53 levels, BE.EP.DD

Abstract

So far, only a few studies have analysed the presence, pattern, and functional impacts of epigenetic alterations in the mitochondrial genome. However, the possibility that epigenetic alterations could impact mtDNA expression and several mitochondrial functions shouldnot be overlooked. Recent studies have found evidence of mitochondrial isoforms of DNA metiltransferases (DNMTs) and ten-eleven translocation methylcytosineoxigenases (TETs). In addition, targeting of DNA methyltransferases to mitochondria cause alterations in the mtDNA methylation pattern, suggesting a functional role for these enzymes in the mitochondrial context. Interestingly, cells with higher expression of PGC1± and NRF1 show higher mitochondrial localization of DNA methyltransferase 1 (DNMT1). In contrast, higher p53expression results in lower mitochondrial DNMT1content. PGC1± and NRF1 are stress-response transcriptional regulators of several relevant pathways, including mitochondrial proliferation and oxidative stress response, while p53, in addition to its countless functions related to genome maintenance, acts as transcriptional inhibitor of PGC1± and DNMT1. Furthermore, targeting of DNMT1 to mitochondria altered the mtDNA methylation pattern and modulated expression of the mitochondrial genes, depending on their location in the light or heavy chain of the mtDNA, suggesting that mtDNA methylation may regulate mitochondrial function in a p53/PGC1±/NRF1 dependent manner.Considering that we have previously shown that p53 modulates mitochondrial oxidative stress in human cells, we propose to investigate:i) if there are alterations in the mtDNA methylation pattern in response to oxidative stress induced by hydrogen peroxide; ii) if the alterations in the mtDNA methylation pattern are coordinated by DNMTs in the context of oxidative stress; iii) what are impacts of the p53/PCG1±/NRF1 axis in the mtDNA methylation in response of the oxidative stress; and iv) which are the functional impacts in mitochondrial metabolism caused by alterations in mtDNA methylation pattern. (AU)