Mitochondrial dysfunction in type 2 diabetes mellitus: an organ-based analysis

Abstract

Type 2 diabetes mellitus (T2DM) is a systemic disease characterized by hyperglycemia, hyperlipidemia, and organismic insulin resistance. This pathological shift in both circulating fuel levels and energy substrate utilization by central and peripheral tissues contributes to mitochondrial dysfunction across organ systems. The mitochondrion lies at the intersection of critical cellular pathways such as energy substrate metabolism, reactive oxygen species (ROS) generation, and apoptosis. It is the disequilibrium of these processes in T2DM that results in downstream deficits in vital functions, including hepatocyte metabolism, cardiac output, skeletal muscle contraction, β-cell insulin production, and neuronal health. Although mitochondria are known to be susceptible to a variety of genetic and environmental insults, the accumulation of mitochondrial DNA (mtDNA) mutations and mtDNA copy number depletion is helping to explain the prevalence of mitochondrial-related diseases such as T2DM. Recent work has uncovered novel mitochondrial biology implicated in disease progressions such as mtDNA heteroplasmy, noncoding RNA (ncRNA), epigenetic modification of the mitochondrial genome, and epitranscriptomic regulation of the mtDNA-encoded mitochondrial transcriptome. The goal of this review is to highlight mitochondrial dysfunction observed throughout major organ systems in the context of T2DM and to present new ideas for future research directions based on novel experimental and technological innovations in mitochondrial biology. Finally, the field of mitochondria-targeted therapeutics is discussed, with an emphasis on novel therapeutic strategies to restore mitochondrial homeostasis in the setting of T2DM.

Keywords: diabetes mellitus; mitochondria dysfunction.

Fig. 1.

Mitochondria dysfunction across organ systems in type 2 diabetes mellitus. Structural, functional, and molecular changes to mitochondria in multiple diabetic models are displayed. Green font indicates an increase in the change, whereas red font indicates a decrease in the change. ATP_max, maximal ATP synthesis rate; CNS, central nervous system; DRG, dorsal root ganglia; ETC, electron transport chain; MAM, mitochondria-associated ER membrane; MFN1, mitofusin 1; mPTP, mitochondrial morphology and permeability transition pore; OXPHOS, oxidative phosphorylation; PCr, phosphocreatine; PGC-1α, peroxisomal proliferator activator receptor-γ coactivator-1α; PNS, peripheral nervous system; ROS, reactive oxygen species; SOD2, superoxide dismutase 2; UCP2, uncoupling protein 2.

Fig. 2.

mtDNA variation and epigenetic and epitranscriptomic regulation of the mitochondrion. An example of mtDNA variation in the ND1 gene that is associated with increased risk of type 2 diabetes mellitus is shown (Ensembl; left) (96, 176, 207). An example of specific mtDNA CpG sites in the D-Loop found to be methylated is shown (UCSC Genome Browser; top) (103). An example of specific N1-methyladenosine (m¹A) modifications of mtDNA-encoded MT-CO3 mRNA is shown (NCBI; right) (95). 5mC, 5-methylcytosine.