Mitochondrial dysfunction in diabetic ulcers: pathophysiological mechanisms and targeted therapeutic strategies

Abstract

Diabetic foot ulcers (DFUs) are a serious complication of diabetes, characterized by delayed wound healing, recurrent infection, and risk of amputation. Mitochondrial dysfunction has emerged as a central pathological mechanism underlying impaired wound healing. Persistent hyperglycemia triggers a cascade of mitochondrial abnormalities like disrupted calcium homeostasis, excessive ROS production, impaired autophagy, increased apoptosis, and imbalanced mitochondrial dynamics. These alterations hinder ATP production, damage repair cells and delays tissue regeneration. This review comprehensively explores the mechanism of action of oxidative stress, mitochondrial apoptosis, autophagy dysfunction, calcium imbalance and ferroptosis on DFU pathogenesis. It also highlights promising mitochondrial targeted therapies. As mitochondria regulates key cellular processes, targeting mitochondrial dysfunction represents a novel and promising strategy. Future research should focus on integrated approaches to restore mitochondrial homeostasis in diabetic wound healing.

Keywords: ROS; apoptosis; diabetes; mitochondria; trauma.

FIGURE 1

Hyperglycemia-affected cell with high ROS production triggers mitochondrial dysfunction, exacerbates oxidative stress, promotes the formation of AGEs, and further activates signalling pathways, such as NF-κB and PKC, which ultimately leads to delayed wound healing. Hyperglycemia induces the accumulation of AGEs, leading to increased levels of ROS, which in turn downregulates mitochondrial autophagy proteins such as PINK1/Parkin. As the autophagosome cannot fuse with the lysosome properly, mitochondrial degradation is blocked, which ultimately leads to non-healing wound in diabetes mellitus. Damaged mitochondria are not effectively cleared, which further exacerbates oxidative stress and disrupts cellular metabolism.

FIGURE 2

Imbalance of mitochondrial fission and fusion in delayed diabetic wound healing. In a hyperglycaemic environment, mitochondrial fission is increased, while mitochondrial fusion is decreased. This leads to mitochondrial fragmentation, energy deficit (decreased ATP) and ROS production. Since diabetic wounds have a high energy demand, inadequate ATP supply and imbalance in mitochondrial quality control lead to prolonged non-healing of diabetic wounds.

FIGURE 3

Role of mitochondrial apoptosis in non-healing diabetic wounds. Activation of the AGEs/RAGE axis induces overproduction of ROS, leading to upregulation of Bax and downregulation of Bcl-2. The subsequent opening of the mitochondrial membrane permeability transition pore (mPTP) triggers a decrease in ΔΨm, which leads to the release of Cyt C and activation of the caspase cascade reaction, ultimately inducing apoptosis of fibroblasts, exacerbating tissue repair disorders and delaying healing of diabetic wounds. Hyperglycemia triggers mitochondrial calcium (Ca²⁺) overload through MCU channels. Excess Ca²⁺ triggers ROS accumulation, disrupts mitochondrial membrane potential (ΔΨm), and causes Cyt C release, activates caspase cascade reaction, which ultimately induces apoptosis and leads to delayed diabetic wound healing.

FIGURE 4

Role of ferroptosis in diabetic wounds in non-healing diabetic wounds. Hyperglycemia induces mitochondrial dysfunction, leading to excessive ROS production, reduced GPX4 activity and ETC., abnormalities. Excessive Fe²⁺ accumulation induces the Fenton reaction to produce lipid peroxides, which results in ferroptosis. This damage repair cells and impede wound healing.

FIGURE 5

Sustained hyperglycemia-induced mitochondrial dysfunction–characterized by disrupted calcium homeostasis, excessive ROS production, impaired mitophagy, increased apoptosis and ferroptosis, and altered mitochondrial dynamics–is a central pathological mechanism hindering diabetic wound healing.