Protective Role of Mitochondrial Uncoupling Proteins against Age-Related Oxidative Stress in Type 2 Diabetes Mellitus

Abstract

The accumulation of oxidative damage to DNA and other biomolecules plays an important role in the etiology of aging and age-related diseases such as type 2 diabetes mellitus (T2D), atherosclerosis, and neurodegenerative disorders. Mitochondrial DNA (mtDNA) is especially sensitive to oxidative stress. Mitochondrial dysfunction resulting from the accumulation of mtDNA damage impairs normal cellular function and leads to a bioenergetic crisis that accelerates aging and associated diseases. Age-related mitochondrial dysfunction decreases ATP production, which directly affects insulin secretion by pancreatic beta cells and triggers the gradual development of the chronic metabolic dysfunction that characterizes T2D. At the same time, decreased glucose oxidation in skeletal muscle due to mitochondrial damage leads to prolonged postprandial blood glucose rise, which further worsens glucose homeostasis. ROS are not only highly reactive by-products of mitochondrial respiration capable of oxidizing DNA, proteins, and lipids but can also function as signaling and effector molecules in cell membranes mediating signal transduction and inflammation. Mitochondrial uncoupling proteins (UCPs) located in the inner mitochondrial membrane of various tissues can be activated by ROS to protect cells from mitochondrial damage. Mitochondrial UCPs facilitate the reflux of protons from the mitochondrial intermembrane space into the matrix, thereby dissipating the proton gradient required for oxidative phosphorylation. There are five known isoforms (UCP1-UCP5) of mitochondrial UCPs. UCP1 can indirectly reduce ROS formation by increasing glutathione levels, thermogenesis, and energy expenditure. In contrast, UCP2 and UCP3 regulate fatty acid metabolism and insulin secretion by beta cells and modulate insulin sensitivity. Understanding the functions of UCPs may play a critical role in developing pharmacological strategies to combat T2D. This review summarizes the current knowledge on the protective role of various UCP homologs against age-related oxidative stress in T2D.

A Review of Fibraurea tinctoria and Its Component, Berberine, as an Antidiabetic and Antioxidant

“…UCP2 is associated with DM [ 251 ]. UCP2 may be a promising therapeutic target for treating type 2 diabetes mellitus because it regulates insulin secretion and beta-cell dysfunction [ 252 ]. Since UCP2 plays a role in reducing ROS production, the selective activation of UCP2 may have therapeutic potential in patients with diabetes [ 253 ].…”

A Pathophysiological Intersection of Diabetes and Alzheimer’s Disease

“…Another factor correlating diabetes to AD is mitochondrial malfunctioning [ 6 , 16 , 76 ]. Mitochondrial activity is essential for normal neuronal functioning regarding ATP synthesis and for controlling calcium homeostasis [ 97 ].…”

“…Many studies confirmed that patients with impaired glucose tolerance and diabetes have an increased risk of developing Alzheimer’s disease (AD) compared to healthy individuals [ 3 , 4 , 5 ]. The association between diabetes and its effects on the development of retinopathy, neuropathy, nephropathy, and cardiovascular diseases is well established [ 6 ]. However, the underlying processes of how diabetes impacts the brain, cognition, and mental health are not yet fully understood.…”

“…AD and diabetes share many different pathologies, such as hyperglycemia, glucose intolerance, hyperinsulinemia, insulin resistance, adiposity, hypertension, atherosclerosis, and cognitive impairment [ 10 , 11 , 12 ]. The main bases for their development are proposed to be the malfunctioning of insulin signaling [ 13 ] with glucose metabolism disorders, deficits in mitochondrial activity, and cholesterol-associated pathologies—these are some of the many additional causes that have been observed by diabetes researchers and neuroscientists in recent decades [ 6 , 14 , 15 , 16 , 17 ]. In the following sections, we will look at each of the proposed factors causing diabetes and/or AD and find their correlations.…”

Comprehensive Analysis of circRNA Expression Profiles in Human Brown Adipose Tissue

“… 3 The primary function of WAT is storing triglyceride, while BAT, in contrast to WAT, dissipates the energy of chemical bindings through uncoupling protein 1 (UCP1) that results in increased fatty acid oxidation and thermogenesis. 4 , 5 Biologically active BAT can promote thermogenesis through UCP1, and activation of BAT and induction of WAT browning accelerates glycolipid uptake, and is essential for improving lipid metabolism and insulin resistance. 6 However, beige adipose tissue has the characteristics of both WAT and BAT, which can store triglyceride and promote thermogenesis after cold stimulation.…”