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.

FIG. 1.

The primary proteins responsible for mitochondrial fission and fusion. (A) Mitochondrial fission is facilitated by the large GTPase DLP1/Drp1. DLP1/Drp1 recognizes the outer mitochondrial membrane resident receptors Mff, Fis1, or MIEF1/MiD49/51. (B) Outer mitochondrial membrane fusion is promoted by the tethering of adjacent mitochondria through the HR2 domains and GTPase activity of the outer mitochondrial membrane resident Mitofusins (Mfns). OPA1, resident to the inner mitochondrial membrane, supports inner mitochondrial membrane fusion. Proteolytic processing of the OPA1 protein results in both l-OPA1 (long) and s-OPA1 (short) variants. OPA1 is also implicated in cristae remodeling. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

The amplification of mitochondrial insult and dysfunction in diabetic conditions. Hyperglycemia and hyperlipidemia are two hallmarks of diabetes, both of which can hyperpolarize mitochondria causing electron slippage and enhanced reactive oxygen species (ROS) production. Iterative rounds of excess metabolic flux modify the mitochondrial proteome, genome, and lipidome through ROS-mediated oxidative modifications, impairing mitochondrial function. Cumulative damage to mitochondria triggers the next pathologic phase of ROS production from impaired respiratory complexes, which further exacerbates mitochondrial dysfunction and ROS production through a vicious amplifying cycle (denoted by red arrows). The impairment of mitochondrial energetics impedes high-fat metabolism by β-oxidation, resulting in steatosis. Cardiac steatosis promotes wall stiffening, thereby decreasing cardiac function. It also leads to inflammation and fibrosis in an oxidative environment. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Disordered left ventricular intrafibrillar mitochondria with a poor cristae structure developed between 3 and 5 weeks of type I diabetes. Electron microscopy was used to observe the mitochondrial morphology of left ventricular samples from age-matched male mice injected with streptozotocin. Cardiac tissue from 3-week diabetic mice displayed a “normal” morphological appearance of IFM, tightly packed between myofibrils with electron dense matrices and organized cristae (top panel). Mice diabetic for 5 weeks exhibited an altered morphologic appearance with vacuous mitochondria possessing poorly developed cristae (bottom panel).

FIG. 4.

A change in the relative amount of l- and s-OPA1 in diabetic progression of cardiac tissue. OPA1 exists in full length, l-OPA1, or proteolytically cleaved forms, s-OPA1. A mixture of the two is presumably required to support IMM fusion and cristae junction formation. Immunoblotting of left ventricular samples shows a marked increase in s-OPA1 with a concomitant decrease in l-OPA1 in 5-week diabetic mice compared with 3-week diabetic mice (*p≤0.05), demonstrating the enhanced cleavage of OPA1 during disease progression.

FIG. 5.

Mitochondrial dysfunction occurs between 3 and 5 weeks after the onset of type I diabetes. Permeabilized cardiac myofibers were assessed for their propensity to produce ROS with succinate as a substrate. H₂O₂ emission was monitored using amplex red in saponin-permeabilized cardiac myofibers from 3- to 5-week diabetic mice. The rate of ROS emission was normalized with respect to a hydrogen peroxide standard and the weight of the permeabilized myofiber. No significant differences in the rate of H₂O₂ emission were observed at 3 weeks relative to the control, whereas they were significantly increased (*p≤0.05) in myofibers from 5 week diabetic animals. The increased ROS production in the 5-week diabetic hearts was still present with rotenone that blocks reverse electron flow to complex I, indicating the increased ROS production in forward electron flow. The increases of ROS emission by both forward and reverse electron transport suggest overall impairment of respiratory complexes in 5-week diabetic hearts.

FIG. 6.

Inhibition of mitochondrial fission protects the cardiac cell under early and late stages of diabetes progression. The formation of short and small mitochondria in metabolic excess is an early event associated with ROS increase. Cumulative oxidative insult causes mitochondrial dysfunction and pathological fragmentation/swelling of mitochondria, leading to further oxidative injury. Imposing suppression of mitochondrial fission at an early stage of progression eliminates mitochondrial shortening and ROS increase. At later stages of progression, fission inhibition would also be protective by preventing an increase in cell death. Accordingly, the inhibition of fission or targeted elongation of mitochondria in cells challenged with excess substrate would reduce oxidative tissue injury. HF, high fat; HG, high glucose.

FIG. 7.

Controlling the extent of fission inhibition can modulate ROS and oxidative stress while maintaining mitochondrial function. Sufficiently weak inhibition of mitochondrial fission would induce mild uncoupling without compromising mitochondrial function while relieving the ROS-induced oxidative stress. By this means, mitochondrial morphology could serve as a controlling factor of mitochondrial function. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars