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.

Background Diabetes mellitus is a chronic disease that impacts an increasing percentage of people each year. Among its comorbidities, diabetics are two to four times more likely to develop cardiovascular diseases. While HbA1c remains the primary diagnostic for diabetics, its ability to predict long-term, health outcomes across diverse demographics, ethnic groups, and at a personalized level are limited. The purpose of this study was to provide a model for precision medicine through the implementation of machine-learning algorithms using multiple cardiac biomarkers as a means for predicting diabetes mellitus development. Methods Right atrial appendages from 50 patients, 30 non-diabetic and 20 type 2 diabetic, were procured from the WVU Ruby Memorial Hospital. Machine-learning was applied to physiological, biochemical, and sequencing data for each patient. Supervised learning implementing SHapley Additive exPlanations (SHAP) allowed binary (no diabetes or type 2 diabetes) and multiple classification (no diabetes, prediabetes, and type 2 diabetes) of the patient cohort with and without the inclusion of HbA1c levels. Findings were validated through Logistic Regression (LR), Linear Discriminant Analysis (LDA), Gaussian Naïve Bayes (NB), Support Vector Machine (SVM), and Classification and Regression Tree (CART) models with tenfold cross validation. Results Total nuclear methylation and hydroxymethylation were highly correlated to diabetic status, with nuclear methylation and mitochondrial electron transport chain (ETC) activities achieving superior testing accuracies in the predictive model (~ 84% testing, binary). Mitochondrial DNA SNPs found in the D-Loop region (SNP-73G, -16126C, and -16362C) were highly associated with diabetes mellitus. The CpG island of transcription factor A, mitochondrial (TFAM) revealed CpG24 (chr10:58385262, P = 0.003) and CpG29 (chr10:58385324, P = 0.001) as markers correlating with diabetic progression. When combining the most predictive factors from each set, total nuclear methylation and CpG24 methylation were the best diagnostic measures in both binary and multiple classification sets. Conclusions Using machine-learning, we were able to identify novel as well as the most relevant biomarkers associated with type 2 diabetes mellitus by integrating physiological, biochemical, and sequencing datasets. Ultimately, this approach may be used as a guideline for future investigations into disease pathogenesis and novel biomarker discovery. Electronic supplementary material The online version of this article (10.1186/s12933-019-0879-0) contains supplementary material, which is available to authorized users.

Nano‐titanium dioxide (nano‐TiO2) is one of the most prevalently utilized ENMs. However, little is known regarding the ramifications that maternal inhalation exposure during gestation can have on growing progeny. Mitochondrial bioenergetics are critical for the maintenance of sufficient ATP for cardiac contractile function and data suggest that ENM exposure can cause deficits in this important mitochondrial role. Further, ENM inhalation exposure has been associated with an increase in mitochondrially‐derived reactive oxygen species (ROS). Nevertheless, it is unclear if such a dynamic occurs in the growing fetus or whether ROS is involved in fetal epigenome remodeling. The purpose of this study was to determine how maternal ENM exposure influences fetal ROS and epigenomic remodeling in a mouse model. Wild‐type pregnant dams were exposed to nano‐TiO2 with an aerodynamic diameter of 156 ± 2 nm and a mass concentration of 12 mg/m3 starting at gestational day 5 (GD 5), for 6 hours over 6 non‐consecutive days. Echocardiographic imaging was used to asses cardiac dysfunction in maternal, fetal (GD 16–19), and young adult (10–12 weeks) contexts. Electron transport chain complex (ETC) activities, mitochondrial size, complexity, and respiration were assessed. 5‐methylcytosine, and Dnmt1 protein and Hif1‐α activity, central contributors to epigenomic remodeling, were assessed. Cardiac function assessment revealed a 43% increase in left ventricular mass, 25% decrease in cardiac output in fetal pups, and 18.2% decrease in fractional shortening in young adult pups. In fetal pups, ROS levels were significantly increased (~10 fold) with a subsequent decrease in mitochondria phospholipid hydroperoxide glutathione peroxidase (mPHGPx) expression. ETC complex activity IV was decreased 68% and 46% in fetal and adult hearts, respectively. DNA Methylation was significantly increased in fetal pups following exposure, along with increased Hif1‐α activity and Dnmt1 protein expression. Significant increases in mitochondrial size and internal complexity persisted into adulthood following exposure. Maternal exposure to nano‐ TiO2 during gestation results in adverse effects on cardiac function by causing an increase in ROS levels and associated dysregulation via a Hif1‐α/Dnmt1 regulatory axis in the fetal offspring. The elevated ROS levels results in mitochondrial dysfunction at the fetal stage, which precipitates alterations in mitochondrial structure and persistent cardiac dysfunction. Our findings suggest a distinct interplay between ROS signaling and epigenetic remodeling that lead to sustained cardiac contractile dysfunction in growing and adult offspring mice following maternal ENM exposure. Support or Funding Information Supported by: RO1 HL‐128485 (JMH), RO1‐ES015022 (TRN), AHA‐17PRE33660333 (QAH). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.