Mitochondrial Dynamics in Diabetic Cardiomyopathy

Abstract

Significance: Cardiac function is energetically demanding, reliant on efficient well-coupled mitochondria to generate adenosine triphosphate and fulfill the cardiac demand. Predictably then, mitochondrial dysfunction is associated with cardiac pathologies, often related to metabolic disease, most commonly diabetes. Diabetic cardiomyopathy (DCM), characterized by decreased left ventricular function, arises independently of coronary artery disease and atherosclerosis. Dysregulation of Ca 2+ handling, metabolic changes, and oxidative stress are observed in DCM, abnormalities reflected in alterations in mitochondrial energetics. Cardiac tissue from DCM patients also presents with altered mitochondrial morphology, suggesting a possible role of mitochondrial dynamics in its pathological progression. Recent Advances: Abnormal mitochondrial morphology is associated with pathologies across diverse tissues, suggesting that this highly regulated process is essential for proper cell maintenance and physiological homeostasis. Highly structured cardiac myofibers were hypothesized to limit alterations in mitochondrial morphology; however, recent work has identified morphological changes in cardiac tissue, specifically in DCM. Critical Issues: Mitochondrial dysfunction has been reported independently from observations of altered mitochondrial morphology in DCM. The temporal relationship and causative nature between functional and morphological changes of mitochondria in the establishment/progression of DCM is unclear. Future Directions: Altered mitochondrial energetics and morphology are not only causal for but also consequential to reactive oxygen species production, hence exacerbating oxidative damage through reciprocal amplification, which is integral to the progression of DCM. Therefore, targeting mitochondria for DCM will require better mechanistic characterization of morphological distortion and bioenergetic dysfunction. Antioxid. Redox Signal. 22, 1545Signal. 22, -1562

Mitochondrial quality control in the diabetic heart

“…Increasing Opa1 protein levels or reducing Opa1 O-GlcNAcylation blocks high glucose-induced mitochondrial fragmentation and dysfunction[48], further supporting a detrimental role of mitochondrial fragmentation in high glucose toxicity. In the diabetic mouse heart, STZ type 1 diabetes induces the fragmentation of interfibrillar mitochondria as assessed by light scattering [67] and electron microscopy [68], which is associated with increased proteolytic cleavage of Opa1 [69]. Coronary endothelial cells isolated from STZ diabetic mice also show increased Drp1, reduced Opa1 and enhanced mitochondrial fission [70].…”

“…Significantly, decreased expression of Mfn1 and Atg5 as well as enhanced mitochondrial fragmentation are seen in the right atria of type 2 diabetic patients[71]. Functionally, the increased mitochondrial fission has been proposed to be responsible for enhanced ROS production in diabetic cardiomyopathy [69]. This is supported by the ability of Drp1-K38A mutant to attenuate oxidative stress in the liver and the kidney of STZ diabetic mice [72].…”

Mitochondrial health, the epigenome and healthspan

“…Various mitochondrial network functions emerge from a dynamic interplay between all these aspects. For example, the predominance of fission over fusion in glucose and lipid excess happens concomitantly with higher expression of fission proteins [41], or the occurrence of mitochondrial membrane potential (ΔΨ m ) and NAD(P)H oscillations occurring with intense oxidative stress and overwhelming of the antioxidant systems [15, 19, 42]. …”

“…Mitochondria also maintain an anterograde and retrograde signaling cross-talk with the nucleus that generates reciprocal activation-repression patterns of gene expression [4, 44, 49]. Mitochondria can determine apoptotic and necrotic cell death mediated by Ca 2+ overload and opening of the permeability transition pore [19, 50, 51], and their turnover is modulated by the mitochondrial quality control machinery including the fission-fusion, mitophagy and biogenesis processes [41, 52–54]. …”

“…Increasing evidence shows that the health status of the mitochondrial network in mammalian tissues is highly sensitive to the cellular energy/redox capacity [45, 58], fusion-fission dynamics [41], and mitochondrial turnover as a result of the dynamic balance between mitochondrial loss vs. scavenging and replacement, e.g., by mitophagy [52] and biogenesis [54, 59]. Alterations of mitochondrial quality control due to altered fusion-fission dynamism and mitophagy can explain differences in cumulative mitochondrial damage.…”