Hypermethylation of Hepatic Mitochondrial ND6 Provokes Systemic Insulin Resistance

Abstract

Mitochondrial epigenetics is rising as intriguing notion for its potential involvement in aging and diseases, while the details remain largely unexplored. Here it is shown that among the 13 mitochondrial DNA (mtDNA) encoded genes, NADH‐dehydrogenase 6 (ND6) transcript is primarily decreased in obese and type 2 diabetes populations, which negatively correlates with its distinctive hypermethylation. Hepatic mtDNA sequencing in mice unveils that ND6 presents the highest methylation level, which dramatically increases under diabetic condition due to enhanced mitochondrial translocation of DNA methyltransferase 1 (DNMT1) promoted by free fatty acid through adenosine 5’‐monophosphate (AMP)‐activated protein kinase (AMPK) activation. Hepatic knockdown of ND6 or overexpression of Dnmt1 similarly impairs mitochondrial function and induces systemic insulin resistance both in vivo and in vitro. Genetic or chemical targeting hepatic DNMT1 shows significant benefits against insulin resistance associated metabolic disorders. These findings highlight the pivotal role of ND6 epigenetic network in regulating mitochondrial function and onset of insulin resistance, shedding light on potential preventive and therapeutic strategies of insulin resistance and related metabolic disorders from a perspective of mitochondrial epigenetics.

Identification of immune and stromal cell infiltration-related gene signature for prognosis prediction in acute lymphoblastic leukemia

“…In terms of each gene, the higher expression of all seven ISCIRGs was positively associated with shorter OS time. The major function of the seven genes included: LILRA1 is to regulate immune responses by interacting with MHC class I ligands [ 31 ]; NRGN is a postsynaptic protein kinase substrate that binds calmodulin in the absence of calcium [ 32 ]; VPREB3 and IGHM is thought to be involved in B cell maturation [ 33 ], mutation or absence can cause either an arrest or a severe impairment at the pro-B cell stage [ 34 , 35 ]; MT-ND6 involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly [ 36 ]; EMP2 regulates cell membrane composition, and up-regulation of this gene has been linked to cancer progression in multiple different tissues [ 37 , 38 ]; and FFAR1 involved in the metabolic regulation of insulin secretion [ 39 ]. In terms of the synergies of these genes, the results of PPI network analysis and functional enrichment analysis for the seven DEGs showed that these genes were mainly enriched in mitochondrial electron transport and oxidative phosphorylation.…”

Contribution of mitochondrial gene variants in diabetes and diabetic kidney disease

“…Mitochondrial respiratory Complex I plays an important role in the process of ATP synthesis, which is the rate-limiting enzyme in electron transport chain (ETC) ( 73 , 74 ). Current evidence suggests that the defects in complex I may be associated with metabolic diseases, including diabetes, IR, and NAFLD ( 3 – 5 ). In addition, complex I is also a major source of reactive oxygen species (ROS) in mitochondria ( 75 ), which has been implicated in the pathology of Parkinson disease ( 76 ) and ageing ( 77 ).…”

“…In the process of insulin synthesis, mitochondria not only provide the necessary ATP for insulin exocytosis but also have a core function in glucose sensing and the induction of triggering and amplifying signals that adjust insulin secretion to glycaemia. Variants in the mitochondrial genomes are related to a cluster of metabolic diseases, including mitochondrial diabetes, insulin resistance (IR), non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome (MetS) (3)(4)(5)(6). Single mtDNA variants are associated with type 2 diabetes mellitus (T2DM).…”

Hepatic Suppression of Mitochondrial Complex II Assembly Drives Systemic Metabolic Benefits

“…Glucose and Insulin Tolerance Tests: GTT and ITT were performed following previously published study. [52] For GTT, mice were fasted overnight and administered glucose (2 g kg −1 ), blood glucose levels were measured at 0, 15, 30, 45, 60, 90, and 120 min. For ITT, mice were fasted for 6 h and administered insulin intraperitoneally (0.7 U kg −1 for chow diet and 0.75 U kg −1 for HFD), blood glucose was measured at 0, 15, 30, 45, 60, 90, and 120 min.…”