Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression

Abstract

Type 2 diabetes (T2D) is a heterogenous disease, and conventionally, peripheral insulin resistance (IR) was thought to precede islet β-cell dysfunction, promoting progression from prediabetes to T2D. New evidence suggests that T2D-lean individuals experience early β-cell dysfunction without significant IR. Regardless of the primary event (i.e., IR vs. β-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may be a driver of T2D onset and progression. Oxidative stress, defined as the generation of reactive oxygen species (ROS), is mediated by hyperglycemia alone or in combination with lipids. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress promotes inter-tissue mis-communication, and new evidence suggests that this is mediated via extracellular vesicles (EVs), including mitochondria containing EVs. Under metabolic-related stress conditions, EV-mediated cross-talk between β-cells and skeletal muscle likely trigger mitochondrial anomalies leading to prediabetes and T2D. This article reviews the underlying molecular mechanisms in ROS-related pathogenesis of prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress. Further, this review will describe the potential of various therapeutic avenues for attenuating oxidative damage, reversing prediabetes and preventing progression to T2D.

Keywords: extracellular vesicles; insulin resistance; islet beta cells; mitochondria; oxidative stress; prediabetes; type 2 diabetes.

Figure 1

Phenotypic and Clinical manifestation of T2D heterogenous populations. Classification of T2D based upon specific characteristics features including fat accumulation, insulin action, β-cell function, multi-omics biomarkers and disease progression. Created with BioRender.com.

Figure 2

Mechanisms of chronic ROS/RNS generation in dysfunctional mitochondria. Exposure of cells to diabetogenic conditions like hypoxia, inflammation, hyperglycemia, and overproduction of free fatty acids can lead to increased leakage of electrons from the mitochondrial ETC. This enhanced electron leakage results in the overproduction of ROS/RNS, which can lead to oxidative stress and cellular damage. Created with BioRender.com.

Figure 3

Transient ROS signaling in the healthy islet β-cell. (1) Glucose metabolism increases the levels of ROS in a transient manner, which triggers signaling events that ultimately culminating in GSIS. (2) The increased levels of ROS (H₂O₂) activate ryanodine receptors (RyRs) at the surface of endoplasmic reticulum, which causes the release of Ca²⁺ sufficient enough to trigger GSIS. (3) NOX4 at the mitochondrial surface causes an increase in ROS that causes the closure of ATP sensitive potassium channel and ensuing GSIS. (4) The plasma membrane associated NOX2 activation requires GTPase signaling cascades that lead to mobilization of insulin secretory granules towards the plasma membrane for release of insulin. Created with BioRender.com.

Figure 4

Differential mechanisms involved in the contribution of mitophagy associated with various stages of skeletal muscle IR. Mitophagy is a specialized form of macro-autophagy that selectively disposes of aging, damaged or dysfunctional mitochondria via autophagolysosomes-mediated degradation. (a) Ubiquitin-dependent mitophagy relies upon the stabilization of PINK1 on the OMM upon mitochondrial membrane damage and/or decrease of membrane potential. PINK1 autoactivation via Ser 228 and 405 autophosphorylation enables Ser 65 phosphorylation of ubiquitin on OMM proteins to recruit PARKIN. PINK1 activation of PARKIN via Ser 65 phosphorylation activates its E3-ubiquitin ligase activity triggering a feedback loop of further Ser 65 phosphorylation of polyubiquitin chains on OMM proteins and recruitment of more PARKIN. The ser-65 phosphorylated polyubiquitin chains of the OMM proteins facilitate LC3-positive autophagosome recruitment via LC3 interacting adaptor proteins. (b) Receptor-dependent mitophagy relies upon OMM and inner mitochondrial membrane (IMM) proteins with LC3-interacting motif regions such as FUNDC1 and BNIP3L/NIX that directly bind to LC3 enabling mitochondria-autophagosome fusion. (c) Proposed model for mitophagy role in T2D where increased mitophagy acts as a protective early response to protect against accumulative mitochondrial damage via ROS production, whilst T2D muscle the decreased mitophagy activity enables damaged mitochondria accumulation. Whether STX4 regulates mitophagy via a PARKIN-dependent or -independent pathway remains in question (?). Created with BioRender.com.

Figure 5

Mechanisms of skeletal muscle ROS generation in T2D. Hyperglycemia-mediated mitochondrial defects and the activation of stress pathways increase ROS in skeletal muscle, which then contributes to islet cell damage/dysfunction. GSH: glutathione; SOD: superoxide dismutase; NADPH: nicotinamide adenine dinucleotide phosphate; AGE: advanced glycation end products; PKC: protein kinase C; DAG: diacyl glycerol; NF-κB: nuclear factor-kappa-B; PKC; NOX: NADPH oxidases; UDPGlcNAc: uridine diphosphate-N-acetylglucosamine. The (↑) indicates upregulation/increase, and (↓) arrow indicates downregulation/decrease in the stress associated pathways, signaling molecules and antioxidants. All the connecting arrows specify the sequence of cellular responses induced by ROS via elevated levels of extra/intracellular glucose and lipids. Created with BioRender.com.

Figure 6

Islet β-cell-skeletal muscle crosstalk is mediated by EVs. During exercise (a) or IR (b), skeletal muscles secrete EVs which contain numerous secreted factors, including mitochondrial cargo. These factors can impact the health of islet β-cells. Refer to Table 2 for more details. GLP-1, Glucagon-like peptide-1. Solid arrows indicate the release of EVs from the tissues (skeletal muscle and islet β-cell). The dashed arrow and (?) indicates that it remains to be determined as to whether EVs released from an islet β-cell are required to regulate skeletal muscle function. Created with BioRender.com.

Figure 7

Adipose tissue Mito-EV mediated inter-organ communications. Mito-EV cargo impacts whole-body metabolism by influencing pancreatic β-cells and macrophage function. Negative effects (↓) on macrophage lead to impaired insulin stimulated glucose uptake by skeletal muscle myocytes and decreased GSIS from pancreatic β-cells. Positive effect (↑), increased insulin tolerance and sensitivity, or increased GSIS from pancreatic β-cells. Created with BioRender.com.