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Review
. 2021 Aug 17;10(8):2114.
doi: 10.3390/cells10082114.

Selective Autophagy in Hyperglycemia-Induced Microvascular and Macrovascular Diseases

Leena P Bharath  1 , Jack Donato Rockhold  1 , Rachel Conway  1
Affiliations
Review

Selective Autophagy in Hyperglycemia-Induced Microvascular and Macrovascular Diseases

Leena P Bharath et al. Cells. .

Abstract

Dysregulation of autophagy is an important underlying cause in the onset and progression of many metabolic diseases, including diabetes. Studies in animal models and humans show that impairment in the removal and the recycling of organelles, in particular, contributes to cellular damage, functional failure, and the onset of metabolic diseases. Interestingly, in certain contexts, inhibition of autophagy can be protective. While the inability to upregulate autophagy can play a critical role in the development of diseases, excessive autophagy can also be detrimental, making autophagy an intricately regulated process, the altering of which can adversely affect organismal health. Autophagy is indispensable for maintaining normal cardiac and vascular structure and function. Patients with diabetes are at a higher risk of developing and dying from vascular complications. Autophagy dysregulation is associated with the development of heart failure, many forms of cardiomyopathy, atherosclerosis, myocardial infarction, and microvascular complications in diabetic patients. Here, we review the recent findings on selective autophagy in hyperglycemia and diabetes-associated microvascular and macrovascular complications.

Keywords: ER-phagy; autophagy; cardiovascular; diabetes; endoplasmic reticulum; lysosome; mitochondria; mitophagy; pexophagy; pexoxisome; reactive oxygen species (ROS).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Signaling in macroautophagy. The figure depicts some of the prominent signaling pathways of autophagy. The activation of the PI3K/AKT/ERK1/2 kinases promotes the phosphorylation and activation of the mTOR pathway, thereby inhibiting autophagy. AKT activates mTOR by directly phosphorylating and inhibiting TSC2. ERK phosphorylates and functionally inactivates TSC2. ERK can also phosphorylate raptor of the mTORC1 complex and promote the activation of mTOR (red arrow). An increase in calcium within the ER, calmodulin-binding, and stress conditions such as amino acid starvation activates CAMKKβ, which activates AMPK. Energy stress is well known to activate AMPK. AMPK activates ULK1, a mammalian autophagy initiating kinase, which leads to the inhibition of mTORC1, leading to the activation of autophagy (green arrows). In addition, ULK1 can phosphorylate Beclin-1 in association with ATG14 to promote autophagy.
Figure 2
Figure 2
Hyperglycemia dysregulates selective autophagy and promotes diabetic complications. Hyperglycemia induced organelle dysfunction promotes cellular dysfunction. Impaired mitophagy promotes excessive mitochondrial ROS production, impaired mitochondrial energy metabolism, and fuel utilization. Peroxisomal damage results in failure of the redox system within the organelle, dysregulation of fatty acid oxidation, and impaired import of proteins. Protein misfolding within the endoplasmic reticulum (ER) causes the unfolded protein response, which induces ER stress. Hyperglycemia stalls the clearance of the damaged and dysfunctional organelles due to inefficient autophagy. Impaired fusion of the autophagosome with the lysosome, decreased lysosomal acidification, and efficiency leads to the accumulation of dysfunctional organelles, resulting in an unhealthy cellular milieu, promoting diabetic macrovascular and microvascular complications.
Figure 3
Figure 3
Mitochondrial homeostasis is altered by hyperglycemia.
Figure 4
Figure 4
Chronic hyperglycemia disrupts endoplasmic reticulum (ER) homeostasis. When disruption of homeostasis occurs within the ER, the ER initiates the adaptive ER-stress responses such as the unfolded protein response (UPR) and autophagy. Lysosomes engulf portions of damaged ER during micro ERphagy, whereas the autophagy machinery is involved in macro ERphagy. Activation of the adaptive stress responses alleviates stress and restores homeostasis. However, unresolvable UPR activation due to chronic hyperglycemia exhausts the ER stress response, impairs autophagy, and promotes apoptosis.
Figure 5
Figure 5
Suppression of pexophagy and mitophagy promotes exaggerated oxidative stress in hyperglycemic conditions.
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