Multi-Tissue DNA Methylation Remodeling at Mitochondrial Quality Control Genes According to Diet in Rat Aging Models

Patrizia D’Aquila,Dina Bellizzi,Giuseppe Passarino,Francesco De Rango,Francesco Guarasci,Andrea Corsonello,Maurizio Mandalà

doi:10.3390/nu12020460

Patrizia D’Aquila, Dina Bellizzi + Show 5 more

Open Access

https://doi.org/10.3390/nu12020460

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Abstract

An adequate mitochondrial quality control system ensures the maintenance of a healthy mitochondrial pool so as to slow down the progressive accumulation of damage affecting mitochondrial function during aging and diseases. The amount and quality of nutrients availability were demonstrated to induce a process of bioenergetics adaptation by influencing the above system via epigenetic modifications. Here, we analyzed DNA samples from differently-aged rats fed a standard or low-calorie diet to evaluate tissue-specific changes in DNA methylation of CpG sites falling within Polg, Polg2, Tfam, Fis1, and Opa1 genes. We found significant changes according to age and tissue type and the administration of the low-calorie diet is responsible for a prevalent increase in DNA methylation levels. Particularly, this increase was more appreciable when this diet was administered during adulthood and at old age. Regression analysis demonstrated that DNA methylation patterns of the analyzed genes were negatively correlated with their expression levels. Data we obtained provide the first evidence about changes in DNA methylation patterns of genes involved in the mitochondrial biogenesis in response to specific diets and demonstrated that epigenetic modifications are involved in the modulation of mitochondrial dynamics driven by age and nutrition.

Highlights

The progressive accumulation of functional impairments in mitochondrial function has been widely recognized as one of the main hallmarks of aging and age-related diseases [1,2]
Given the pivotal role of mitochondria both in energy metabolism and in producing substrates for DNA methylation and histone modifications as well as the ability of nutrition to induce epigenetic remodeling, we explored in rats whether changes in eating habit during life were able to modulate the methylation status of candidate genes involved in mitochondrial fusion/fission and biogenesis processes
We searched for tissue-specific differences in the methylation status of Cytosine-phosphate-Guanine (CpG) islands falling within pivotal genes previously found to be involved in mitochondrial biogenesis, fusion and fission (Polg, Polg2, Tfam, Fis1 and Opa1) in DNA

Summary

Introduction

The progressive accumulation of functional impairments in mitochondrial function has been widely recognized as one of the main hallmarks of aging and age-related diseases [1,2]. The age-related mitochondrial decline is partially due to a failure in the fine-tune coordination of mitochondrial turnover mechanisms that regulate the morphology, the size and the number of functional mitochondria under a wide variety of both physiological and non-physiological conditions [3,4,5]. These mechanisms include the increase of mitochondrial mass (biogenesis), the division of a mitochondrion in two or more daughter organelles (fission), the merging of healthy and damaged mitochondria (fusion) and the selective clearance of damaged mitochondria via the autophagic pathway (mitophagy) [4,6,7]. Lipid oversupply can alter mitochondrial dynamics [16]

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