Mitochondrial alteration in type 2 diabetes and obesity: an epigenetic link

Abstract

The growing epidemic of type 2 diabetes mellitus (T2DM) and obesity is largely attributed to the current lifestyle of over-consumption and physical inactivity. As the primary platform controlling metabolic and energy homeostasis, mitochondria show aberrant changes in T2DM and obese subjects. While the underlying mechanism is under extensive investigation, epigenetic regulation is now emerging to play an important role in mitochondrial biogenesis, function, and dynamics. In line with lifestyle modifications preventing mitochondrial alterations and metabolic disorders, exercise has been shown to change DNA methylation of the promoter of PGC1α to favor gene expression responsible for mitochondrial biogenesis and function. In this article we discuss the epigenetic mechanism of mitochondrial alteration in T2DM and obesity, and the effects of lifestyle on epigenetic regulation. Future studies designed to further explore and integrate the epigenetic mechanisms with lifestyle modification may lead to interdisciplinary interventions and novel preventive options for mitochondrial alteration and metabolic disorders.

Keywords: epigenetic; lifestyle; mitochondrial alteration; obesity; type 2 diabetes.

Figure 1. Mitochondrial stress in type 2 diabetes and obesity. The current lifestyle of overconsumption and physical inactivity poses a persistent nutrient surplus, leading to mitochondrial stress and the accumulation of reactive oxygen species (ROS) and metabolite intermediates (FFA and DAG) that can trigger oxidative stress and activation of stress-sensitive kinases. Impaired insulin secretion and sensitivity (i.e., the hallmarks of T2DM) occur as a result of stress-induced β-cell dysfunction and insulin resistance. FFA, free fatty acid; DAG, diacylglycerol.

Figure 2. The role of mitochondria in energy metabolism. (A) Mitochondria undergo frequent fusion and fission (the dynamic processes that maintain mitochondrial integrity) and underpin energy homeostasis (ATP generation and thermogenesis) and macromolecule biosynthesis. (B) Energy or nutrient stimuli (e.g., exercise, fasting or calorie restriction) regulate mitochondrial biogenesis and function through pathways involving cAMP-PKA/CREB, AMP/ATP-AMPK, and NAD⁺/NADH-SIRT1. As the key regulator of mitochondria, PGC1α funnels the signaling to NRF1/2-Tfam and upregulates the genes that are associated with mitochondrial oxidative metabolism. cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP response element-binding protein; AMP, 5′-adenosine monophosphate; AMPK, 5′-adenosine monophosphate-activated protein kinase; NAD⁺, nicotinamide adenine dinucleotide; NADH, reduced form of NAD⁺; SIRT1, sirtuin (silent mating type information regulation 2 homolog) 1; PGC1α, peroxisome proliferator-activated receptor γ coactivator 1α; NRF1/2, nuclear respiratory factors 1 and 2; Tfam, mitochondrial transcription factor A.

Figure 3. The epigenetic mechanisms of mitochondrial regulation in T2DM and obesity. Increased DNA methylation represses expression of PGC1α and Tfam, the key regulators of mitochondrial biogenesis. Epigenetic regulation of mitochondrial function includes: (1) DNA hypermethylation that represses the genes of mitochondrial oxidative metabolism (e.g., COX7A1 and NDUFB6); and (2) microRNAs (miR15a, miR133a, and miR-184) that repress mitochondrial substrate carrier (Slc25a22) or uncoupling protein (UCP2). microRNA (miR-106b) was also identified to regulate mitochondrial dynamic protein (Mfn2). Behavioral intervention such as exercise has been shown to change the epigenetic signature (DNA methylation) and improve mitochondrial biogenesis and function through PGC1α and Tfam. The mitochondria-promoting effects have also been reported for dietary intervention, calorie restriction, and weight loss; whether and how an epigenetic mechanism is involved in the mitochondrial regulation deserves further investigation. PGC1α, peroxisome proliferator-activated receptor γ coactivator 1α; Tfam, mitochondrial transcription factor A; UCP2, uncoupling protein 2; Mfn2, mitofusin 2;sirt COX7A1, cytochrome c oxidase subunit VIIa polypeptide 1; NDUFB6, NADH dehydrogenase (ubiquinone) 1 β subcomplex, 6.