Mitochondrial health, the epigenome and healthspan

Abstract

Food nutrients and metabolic supply-demand dynamics constitute environmental factors that interact with our genome influencing health and disease states. These gene-environment interactions converge at the metabolic-epigenome-genome axis to regulate gene expression and phenotypic outcomes. Mounting evidence indicates that nutrients and lifestyle strongly influence genome-metabolic functional interactions determining disease via altered epigenetic regulation. The mitochondrial network is a central player of the metabolic-epigenome-genome axis, regulating the level of key metabolites [NAD(+), AcCoA (acetyl CoA), ATP] acting as substrates/cofactors for acetyl transferases, kinases (e.g. protein kinase A) and deacetylases (e.g. sirtuins, SIRTs). The chromatin, an assembly of DNA and nucleoproteins, regulates the transcriptional process, acting at the epigenomic interface between metabolism and the genome. Within this framework, we review existing evidence showing that preservation of mitochondrial network function is directly involved in decreasing the rate of damage accumulation thus slowing aging and improving healthspan.

Keywords: acetylation; adipose tissue; aging; autophagy; biogenesis; caloric restriction; cardiovascular disease; chromatin; diet; epigenetic modification; epigenetics; histones; mitochondria; mitochondrial fusion–fission; mitophagy.

Figure 1

Morphological appearance of intracellular mitochondrial networks labeled with the cationic potentiometric dye tetramethylrhodamine ethyl ester (TMRE) used to monitor mitochondrial membrane potential. Notice the different architecture exhibited by mitochondrial networks in HeLa, cardiomyocyte and cortical neuron cells ranging from reticular (Hela and neuron) to lattice-like (ventricular cardiomyocyte).

Figure 2. Survival curves according to Gompertz, Weibull and the mixture model of Levy and Levin

The evolutionary biology-based mixture model of Levy and Levin encompasses Gompertz and Weibull components [55]. Notice the increase in the median survival time from the Weibull, to the mixed and the Gompertz distributions (dashed lines). A visible decline in the survival function starts at 35–40y for the Weibull and mixed distributions whereas the decline is only noticeable at about 60–65y for the Gompertz component, accelerating at ~75y, and then showing a steep decline between ~80–90y while approaching an overall rectangular form. At 80y, ~10% and ~35% of the population is alive according to the mixed and Gompertz components, respectively. Prevention of premature deaths (e.g., accidental, neonatal and infant) would bring population survival closer to the Gompertz component of the mixture model. The index of aging-relatedness applied to intrinsic mortality data is a measure of “living life to the fullest” (rectangularization of the survival curve) thus representing a quantitative characterization of health span.

Figure 3. The fluxome and the metabolic-epigenetic-genomic axis

The fluxome corresponds to the fluxes of metabolite transformations from a substrate precursor and the fluxes distribution among different pathways. Lifestyle via diet and exercise or physical activity affect (peri- and postnatally) the balance of energy supply-demand promoting, e.g. over-nutrition or calorie restriction. These interventions have an impact on the fluxome and the levels of metabolites, second messengers, that in turn modify the epigenome via chromatin by, e.g. methylation, acetylation, of the DNA and/or histones. NAD⁺, ATP and AcCoA are key metabolic intermediates in major carbon catabolic pathways and in fuel metabolism, including glucose and pyruvate oxidation, as well as in β-oxidation of fatty acids (FAs). In mammalian cells, AcCoA can be generated both in the mitochondrial and nucleocytoplasmic compartments. In the mitochondria, AcCoA is synthesized from pyruvate by the pyruvate dehydrogenase complex or by β-oxidation, and then feeds into the TCA cycle. A key component of the epigenomic interphase between metabolism and the genome is the assembly of DNA and nucleoproteins that constitutes the chromatin. The chromatin regulates the transcriptional machinery by conformational changes and genome compartmentalization, thus a key component of the epigenomic interphase between metabolism and the genome. Epigenetic modifications regulate the transcriptional and gene expression machinery by conformational changes and genome compartmentalization. Stable patterns of epigenetic modifications may represent a mechanism of cell memory, important for interpreting the long-lasting footprints of hyperglycemic episodes [230] or developmental and nutritional milieus associated with predisposition and progression of disease [62, 80]. The feedback from the genome to the epigenome, exemplified by posttranslational modifications (PTMs) occurring on histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases, and demethylating enzymes, suggests a highly ordered interactive network comprising many components capable of adding and removing modifications at both the chromatin template as well as each other. Key to symbols: fluxome, orange arrows; gene expression, blue arrows.

Figure 4. Substrates fuel interrelationships between main body organs, mitochondria and the epigenome

Depicted are the differential uses of glucose and fatty acids (FAs) by the brain, muscle (cardiac and skeletal), liver and adipose tissue. As shown, the liver appears as a main provider of glucose and FAs for muscle and brain. Adipose tissue provides FAs to the liver; the skeletal muscle can also supply lactate to the liver where it is utilized for gluconeogenesis, especially in the early fed state, when the liver continues in ketogenic and gluconeogenic modes. Displayed is the mitochondrial supply of AcCoA, the main acetyl donor that via its nucleo-cytoplasmic pools determine the autophagic response in mammals [168] and, with a few difference, in yeast as well [162]. The scheme at the center emphasizes that AcCoA excess (red right) or decrease (green bottom) will preclude or stimulate autophagy and gene expression, respectively; decreased autophagy will favor higher mtDNA mutations and heteroplasmy driving accumulation of dysfunctional mitochondria that, in the long-term, will reduce health- and lifespan (red box, top right). Opposite changes will occur under a more balanced AcCoA supply (green box, bottom). Hypothetically, healthy and nutritionally well-adjusted lifestyle, including physical activity or exercise training, would favor balanced energy supply and demand in concert with mitochondrial fusion/fission-driven morphological changes, turnover (mitophagy, biogenesis) and proper energy-redox function [201]. The interplay between these processes would determine not only the overall functionality of the mitochondrial network but also the integrity of the mitochondrial genome [4, 78].