Abstract
Mitochondrial DNA copy number (mtDNAcn) has been proposed for use as a surrogate biomarker of mitochondrial health, and evidence suggests that mtDNA might be methylated. Intermediates of the one-carbon cycle (1CC), which is duplicated in the cytoplasm and mitochondria, have a major role in modulating the impact of diet on the epigenome. Moreover, epigenetic pathways and the redox system are linked by the metabolism of glutathione (GSH). In a cohort of 101 normal-weight and 97 overweight/obese subjects, we evaluated mtDNAcn and methylation levels in both mitochondrial and nuclear areas to test the association of these marks with body weight, metabolic profile, and availability of 1CC intermediates associated with diet. Body composition was associated with 1CC intermediate availability. Reduced levels of GSH were measured in the overweight/obese group (p = 1.3∗10−5). A high BMI was associated with lower LINE-1 (p = 0.004) and nominally lower methylenetetrahydrofolate reductase (MTHFR) gene methylation (p = 0.047). mtDNAcn was lower in overweight/obese subjects (p = 0.004) and independently correlated with MTHFR methylation levels (p = 0.005) but not to LINE-1 methylation levels (p = 0.086). DNA methylation has been detected in the light strand but not in the heavy strand of the mtDNA. Although mtDNA methylation in the light strand did not differ between overweight/obese and normal-weight subjects, it was nominally correlated with homocysteine levels (p = 0.035) and MTHFR methylation (p = 0.033). This evidence suggests that increased body weight might perturb mitochondrial-nuclear homeostasis affecting the availability of nutrients acting as intermediates of the one-carbon cycle.
Highlights
Obesity is a complex disease characterized by a low-grade inflammation status determined by an excessive accumulation of dysfunctional adipose tissue [1]
To disentangle the complex picture between nutrition, epigenetics, and mitochondria in overweight and obesity, we studied a group of 198 subjects (101 controls and 97 overweight or obese persons), with several parameters associated with the 1CC and epigenetic homeostasis having been measured, including the intake of nutrients with an epigenetic impact, blood levels of 1CC intermediates (i.e., folate, betaine, choline, vitamin B12, glutathione (GSH), and homocysteine), the methylation levels of nuclear (i.e., methylenetetrahydrofolate reductase (MTHFR) and LINE-1 repeated elements) and mitochondrial (D-loop) DNA, and the mitochondrial DNA copy number
In terms of MTHFR methylation, we studied a CpG island in the 5′-untranslated (UTR) region of the MTHFR gene spanning from +30 to +184 from the transcription start site, whose methylation levels were found to be inversely correlated with the MTHFR gene expression levels [15, 16, 51]
Summary
Obesity is a complex disease characterized by a low-grade inflammation status determined by an excessive accumulation of dysfunctional adipose tissue [1]. It represents a global health problem since the prevalence of obesity worldwide has reached epidemic proportions [2]. Despite mtDNA being essential for mitochondrial functions, many mitochondrial proteins are encoded by nuclear genes. This keeps mitochondria (and mtDNA) in strict crosstalk with the nuclear DNA [9]
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