Mitochondrial-ferroptotic crosstalk in diabetic Triopathy: a unifying mechanism linking retinal, renal, and neural complications.

Abstract

Diabetes mellitus is a global health burden recognized by progressive microvascular complications, which comprise diabetic retinopathy, nephropathy, and neuropathy, often known as diabetic triopathy. Despite extensive research, the mechanistic convergence of multi-organ damage is not fully understood. Recent studies highlighted that ferroptosis, an iron-dependent form of regulated cell death mediated by lipid peroxidation, plays a crucial role in diabetic tissue damage. Importantly, mitochondria are key modulators of ferroptotic susceptibility because they regulate reactive oxygen species (ROS) production, iron homeostasis, and bioenergetic homeostasis. This review proposes mitochondrial-ferroptotic crosstalk as a unifying mechanistic axis associating retinal, renal, and neural complications in diabetes. We present a comprehensive overview of the molecular basis of ferroptosis through a mitochondria-centered perspective, covering key pathways such as iron homeostasis, the glutathione-GPX4 system, and emerging regulators of ferroptosis such as SLC7A11 and the FSP1-coenzyme Q axis. We also discuss shared vulnerabilities across microvascular tissues, such as mitochondrial dysfunction, iron overload, lipid peroxidation, and chronic inflammation. Tissue-specific evidence supporting ferroptosis in diabetic retinopathy, nephropathy, and neuropathy is discussed critically, with with mitochondrial impairment and redox imbalance emerging as prevalent drivers of the pathophysiology. Finally, we assess current and novel therapeutic approaches targeting the mitochondrial-ferroptotic axis, such as ferroptosis inhibitors, mitochondrial antioxidants, and iron-regulating approaches. Altogether, this integrative model identifies mitochondrial-ferroptotic crosstalk as a key pathogenic mechanism and therapeutic opportunity to mitigate multi-organ complications in diabetes.