Specific therapies must be supported by an optimal understanding of changes in mitochondrial redox state and how it influences other cellular compartments; this field has begun to surface as a therapeutic target for the diabetic heart. We propose an approach based on an alternate mitochondrial electron transport that normalizes the mitochondrial redox state and improves cardiac function in diabetes. Antioxid. Redox Signal. 00, 000-000.

Dysfunction in mitochondrial oxidative phosphorylation (OXPHOS) underlies a wide spectrum of human ailments known as mitochondrial diseases. Deficiencies in complex I of the electron transport chain (ETC) contribute to 30–40% of all cases of mitochondrial diseases, and leads to eye disease including optic nerve atrophy and retinal degeneration. The mechanisms responsible for organ damage in mitochondrial defects may include energy deficit, oxidative stress, and an increase in the NADH/NAD+ redox ratio due to decreased NAD+ regeneration. Currently, there is no effective treatment to alleviate human disease induced by complex I defect.Photoreceptor cells have the highest energy demand and dependence on OXPHOS for survival, and the lowest reserve capacity indicating that they are sensitive to OXPHOS defects. We investigated the effect of mitochondrial OXPHOS deficiency on retinal photoreceptors in a model of mitochondrial complex I defect (apoptosis inducing factor, AIF-deficient mice, Harlequin mice), and tested the protective effect of a mitochondrial redox compound (methylene blue, MB) on mitochondrial and photoreceptor integrity. MB prevented the reduction in the retinal thickness and protein markers for photoreceptor outer segments, Muller and ganglion cells, and altered mitochondrial integrity and function induced by AIF deficiency. In rotenone-induced complex I deficient 661 W cells (an immortalized mouse photoreceptor cell line) MB decreased the NADH/NAD+ ratio and oxidative stress without correcting the energy deficit, and improved cell survival. MB deactivated the mitochondrial stress response pathways, the unfolding protein response and mitophagy. In conclusion, preserving mitochondrial structure and function alleviates retinal photoreceptor degeneration in mitochondrial complex I defect.

Metabolic syndrome increases the risk for cardiovascular disease including metabolic cardiomyopathy that may progress to heart failure. The decline in mitochondrial metabolism is considered a critical pathogenic mechanism that drives this progression. Considering its cardiac specificity, we hypothesized that miR 208a regulates the bioenergetic metabolism in human cardiomyocytes exposed to metabolic challenges. We screened in silico for potential miR 208a targets focusing on mitochondrial outcomes, and we found that mRNA species for mediator complex subunit 7, mitochondrial ribosomal protein 28, stanniocalcin 1, and Sortin nexin 10 are rescued by the CRISPR deletion of miR 208a in human SV40 cardiomyocytes exposed to metabolic challenges (high glucose and high albumin-bound palmitate). These mRNAs translate into proteins that are involved in nuclear transcription, mitochondrial translation, mitochondrial integrity, and protein trafficking. MiR 208a suppression prevented the decrease in myosin heavy chain α isoform induced by the metabolic stress suggesting protection against a decrease in cardiac contractility. MiR 208a deficiency opposed the decrease in the mitochondrial biogenesis signaling pathway, mtDNA, mitochondrial markers, and respiratory properties induced by metabolic challenges. The benefit of miR 208a suppression on mitochondrial function was canceled by the reinsertion of miR 208a. In summary, miR 208a regulates mitochondrial biogenesis and function in cardiomyocytes exposed to diabetic conditions. MiR 208a may be a therapeutic target to promote mitochondrial biogenesis in chronic diseases associated with mitochondrial defects.

No abstract

Metabolic syndrome (abdominal obesity, hyperlipidemia, hyperglycemia, insulin resistance, hypertension, systemic inflammation), usually induced by a high caloric regimen, is a pre‐requisite of type 2 diabetes, and increases the risk for cardiovascular disease. Metabolic syndrome and diabetes induce a specific cardiac phenotype known as metabolic cardiomyopathy, with an early onset as cardiac hypertrophy and diastolic dysfunction that evolves to systolic dysfunction and congestive heart failure. Normal cardiac metabolism exhibits physiologic shifts between glucose and fatty acid (FA) oxidation for ATP production. During a high caloric diet‐induced metabolic syndrome, although an excess of both glucose and FA may be present, the heart becomes almost completely reliant on FA oxidation for ATP production. Primarily driven by the large bloodstream FA availability, this metabolic inflexibility is supported by increased mitochondrial metabolism, and leads to oxidative stress, cardiac inefficiency and dysfunction. The primary molecular trigger of this energetic dysregulation is unknown. We hypothesized that the increase in mitochondrial metabolism is supported by changes in gene expression, and the latter is coordinated by alterations in microRNA expressions. Lewis rats on either a normal or high fat diet (HFD) were compared regarding cardiac structure and function, bioenergetics and gene expression profiling studies followed by validation using Illumina arrays platform and quantitative RT‐PCR. The HFD regimen caused insulin resistance, diastolic dysfunction and cardiac fibrosis. Our microarray studies have highlighted an altered miRNA expression profile in the heart upon HFD with changes in specific miRNAs that regulate insulin sensitivity, mitochondrial metabolism and cardiac pathology (hypertrophy, fibrosis, inflammation). MicroRNA 208a, which is reported to be inversely correlated with cardiac bioenergetics, was found decreased in cardiac tissue upon HFD. We identified targets of miR 208a including the cardioprotective and antioxidant factor stanniocalcin1, nuclear receptor co‐activator 7 (enhances the transcriptional activity of factors involved in mitochondrial biogenesis), mediator complex subunit 7 (regulates the activator‐induced transcription by facilitating the interaction between nuclear receptors, transcriptional co‐activator and co‐repressors, and chromatin modification factors with RNA Pol II), and sorting nexin 10 (mediates the mitochondrial‐endoplasmic reticulum lipid trafficking). Downstream targets of miR 208a, including markers of mitochondrial biogenesis and FA oxidation as well as mitochondrial oxidative phosphorylation with FA substrates, were also increased. CRISPR deletion of the miR 208a in cardiomyocytes led to a bioenergetics profile that favors mitochondrial FA metabolism. In conclusion, our data suggest a role of miR 208a in increasing mitochondrial metabolism and favoring metabolic inflexibility in the heart exposed to HFD. Cardiac metabolic rigidity and dysfunction during metabolic syndrome may be alleviated by controlling the expression of specific miRs involved in cardiac bioenergetics.Support or Funding InformationCMU Early Career Grant, AIREA Grant American Heart AssociationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.