Protective Mechanisms of Mitochondria and Heart Function in Diabetes

Abstract

Significance: The heart depends on continuous mitochondrial ATP supply and maintained redox balance to properly develop force, particularly under increased workload. During diabetes, however, myocardial energeticredox balance is perturbed, contributing to the systolic and diastolic dysfunction known as diabetic cardiomyopathy (DC). Critical Issues: How these energetic and redox alterations intertwine to influence the DC progression is still poorly understood. Excessive bioavailability of both glucose and fatty acids (FAs) play a central role, leading, among other effects, to mitochondrial dysfunction. However, where and how this nutrient excess affects mitochondrial and cytoplasmic energetic/redox crossroads remains to be defined in greater detail. Recent Advances: We review how high glucose alters cellular redox balance and affects mitochondrial DNA. Next, we address how lipid excess, either stored in lipid droplets or utilized by mitochondria, affects performance in diabetic hearts by influencing cardiac energetic and redox assets. Finally, we examine how the reciprocal energetic/redox influence between mitochondrial and cytoplasmic compartments shapes myocardial mechanical activity during the course of DC, focusing especially on the glutathione and thioredoxin systems. Future Directions: Protecting mitochondria from losing their ability to generate energy, and to control their own reactive oxygen species emission is essential to prevent the onset and/or to slow down DC progression. We highlight mechanisms enforced by the diabetic heart to counteract glucose/FAs surplus-induced damage, such as lipid storage, enhanced mitochondria-lipid droplet interaction, and upregulation of key antioxidant enzymes. Learning more on the nature and location of mechanisms sheltering mitochondrial functions would certainly help in further optimizing therapies for human DC. Antioxid. Redox Signal. 22, 1563-1586. Mitochondria and Heart FunctionRedox and energetics of heart function T he heart depends on continuous oxidative metabolism to maintain ATP supply and redox balance for optimal contractile function. More than 90% of heart metabolism is aerobic (166,180). A 70 kg human male at rest consumes 430 L of O 2 per day (177), which can increase 5-to 10-fold depending on physical activity (207). About 90% of this O 2 will be channeled to mitochondrial respiration (166); about 10% of O 2 usage is nonmitochondrial (79). Consequently, mitochondria are central to aerobic life, and their energetic and redox functions are pivotal for health, disease, and aging (36,69,107).Cardiac output measures heart effectiveness as a pump; it can be calculated by multiplying the heart rate (beats/min) by stroke volume (ml/beat). For an average resting heart rate of 72 beats/min and a stroke volume of 70 ml/beat, the cardiac output is *5 L/min. In humans, the average total blood volume is about 5 L; therefore, at rest, one side of the heart pumps all the blood in the body in 1 min (177). The in vivo rate of cardiac basal metabolism is 5-10 time...

Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models

“…An optimal balance between ROS generation and scavenging is needed to maintain contractile function and cardiac myocyte electrophysiology (44,66,67). First, we examined differences in expression of genes involved in ROS generation or scavenging in our mRNA-seq data.…”

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“…citrate, AcCoA) and signaling (e.g., AcCoA, cytochrome c, H 2 O 2 , O 2 ·− ) roles [13, 44]. They influence the cellular redox status introducing ROS, namely H 2 O 2 ) [3, 32, 45–47], and are reciprocally influenced by the cytoplasmic redox environment (e.g., glutathione, H 2 O 2 ) in a dynamic way [46, 48]. Likewise, mitochondria respond to signaling molecules (e.g., Ca 2+ , O 2 ·− , ADP) released from mitochondrial neighbors, other organelles (e.g., endoplasmic or sarcoplasmic reticulum, peroxisomes) or contractile proteins (e.g., myosin ATPase).…”

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Identification of Energy Metabolism Changes in Diabetic Cardiomyopathy Rats Using a Metabonomic Approach

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