Mitochondrial dysfunction, reactive oxygen species, and diabetes mellitus – A triangular relationship: A review

Mia Manojlovic; Sonja Zafirovic; Dragana Tomic Naglic; Edita Stokic; Manfredi Rizzo; Jasjit S. Suri; Esma Isenovic

doi:10.17305/bb.2025.13145

Authors

Mia Manojlovic University of Novi Sad, Faculty of Medicine in Novi Sad, Novi Sad, Serbia; Clinic for Endocrinology, Diabetes and Metabolic Disorders, University Clinical Center of Vojvodina, Novi Sad, Serbia.
Sonja Zafirovic Department of Radiobiology and Molecular Genetics, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
Dragana Tomic Naglic University of Novi Sad, Faculty of Medicine in Novi Sad, Novi Sad, Serbia; Clinic for Endocrinology, Diabetes and Metabolic Disorders, University Clinical Center of Vojvodina, Novi Sad, Serbia.
Edita Stokic University of Novi Sad, Faculty of Medicine in Novi Sad, Novi Sad, Serbia; Clinic for Endocrinology, Diabetes and Metabolic Disorders, University Clinical Center of Vojvodina, Novi Sad, Serbia.
Manfredi Rizzo School of Medicine, Promise Department, University of Palermo, Italy; Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates.
Jasjit S. Suri Stroke Diagnostic and Monitoring Division, AtheroPoint, Roseville, CA, USA; Department of Electrical and Computer Engineering, Idaho State University, Pocatello, ID, USA; Global Biomedical Technologies, Inc., Roseville, CA, USA; Symbiosis Institute of Technology, Nagpur Campus, Symbiosis International (Deemed University), Pune, India.
Esma Isenovic Department of Radiobiology and Molecular Genetics, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia

DOI:

https://doi.org/10.17305/bb.2025.13145

Keywords:

Oxidative stress, reactive oxygen species, mitochondrial dysfunction, diabetes mellitus, cardiovascular complications

Abstract

Diabetes mellitus (DM) disrupts cellular homeostasis and is characterized by mitochondrial structural and functional impairments similar to those found in other metabolic disorders. Mitochondrial dysfunction (MD) leads to the excessive production of reactive oxygen species (ROS), which are central to the progression of cardiovascular (CV) disease—the leading cause of mortality associated with DM. ROS-driven oxidative stress (OS) is implicated in cardiac injury in both clinical and experimental contexts. This review synthesizes recent literature on the role of MD in the development and progression of DM and its associated CV complications, highlighting disrupted pathways that regulate the balance between ROS production and antioxidant defenses. We summarize alterations in mitochondrial dynamics—including fusion, fission, and mitophagy—mtDNA damage, and impaired oxidative phosphorylation characterized by dysregulated mitochondrial membrane potential (ΔΨm), electron transport chain (ETC) defects, uncoupling, and substrate overload. Additionally, we discuss hyperglycemia-activated pathways such as polyol flux, AGE–RAGE interactions, protein kinase C/nicotinamide adenine dinucleotide phosphate (PKC/NADPH) oxidase activation, and poly(ADP-ribose) polymerase 1 (PARP-1)-mediated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibition, which contribute to inflammation, endothelial dysfunction, β-cell failure, insulin resistance, and micro/macrovascular injury. Diagnostic and biomarker strategies encompass mtDNA analysis, bioenergetic assays, metabolomics, proteomics, and imaging techniques including PET, MRI, and NIRS. Therapeutic approaches aimed at restoring mitochondrial function and mitigating OS include mitochondria-targeted antioxidants (such as MitoQ, CoQ10, SkQ1, SS-31, and Mito-TEMPO), metabolic drugs (including metformin and SGLT2 inhibitors), lifestyle modifications, and emerging gene-editing technologies. The interplay between mitochondria, ROS, and DM reflects a tightly regulated aspect of cellular physiology; while targeted and personalized strategies hold promise, they necessitate rigorous evaluation.