| Title | Authors | Year |
|---|---|---|
| Mitochondrial dysfunction, reactive oxygen species, and diabetes mellitus – A triangular relationship: A review | Manojlovic et al. | 2025 |
Overview
The review “Mitochondrial dysfunction, reactive oxygen species, and diabetes mellitus – A triangular relationship” (Manojlovic et al., 2025) characterizes diabetes as a mitochondrial redox disorder driven by substrate overload and oxidative stress.
In the stress–glutamate–ROS model, the same mechanism is triggered by chronic cortisol elevation rather than direct hyperglycemia.
Cortisol increases blood glucose through gluconeogenesis and insulin resistance, while simultaneously amplifying glutamate signaling through NR3C1 activation and vesicular upregulation.
These parallel systems merge in the mitochondria, creating identical patterns of oxidative collapse, calcium overload, and membrane depolarization.
Cortisol as the Link Between Stress and Hyperglycemia
Cortisol’s physiological purpose is to ensure energy availability under stress. It:
- Activates hepatic gluconeogenesis, increasing glucose synthesis from amino acids and glycerol.
- Reduces glucose uptake in muscle and adipose tissue via GLUT4 downregulation, maintaining high plasma glucose.
- Enhances lipolysis and proteolysis, providing substrates for both energy and gluconeogenic conversion.
- Synergizes with epinephrine to mobilize glycogen and maintain elevated glucose during the stress response.
Under chronic activation, these functions lead to a metabolic state resembling prediabetes: continuous glucose elevation, insulin resistance, and mitochondrial saturation.
Mitochondrial Dysfunction Under Hyperglycemia
Manojlovic et al. describe the diabetic mitochondrial phenotype as one of excess substrate flux and redox imbalance, leading to ROS overproduction.
- ETC Overdrive: Elevated NADH/FADH₂ levels drive electron leakage at complexes I and III.
- ΔΨm Collapse: Persistent high potential and proton gradient cause electron backpressure and superoxide generation.
- mtDNA Damage: ROS and lipid peroxidation damage mtDNA near the ETC, impairing complex assembly and amplifying dysfunction.
- Dysregulated Dynamics: Increased fission (Drp1) and reduced fusion (Mfn1/2, OPA1) fragment mitochondrial networks, reducing compensatory capacity.
- Mitophagy Failure: Defective PINK1/Parkin signaling prevents removal of damaged mitochondria, locking the system in oxidative feedback.
- Uncoupling Proteins (UCP1–3): Upregulated by oxidative stress, they discharge ΔΨm and further reduce ATP yield.
This profile represents mitochondrial overextension rather than underuse—identical to excitotoxic neurons that experience sustained depolarization and calcium influx.
ROS Amplification and the Feedback Loop
ROS generation during mitochondrial overload forms a self-reinforcing cycle:
- Electron leakage forms superoxide (O₂•⁻).
- Superoxide converts to H₂O₂ via superoxide dismutase (SOD).
- H₂O₂ and Fe²⁺ via Fenton chemistry yield hydroxyl radicals (•OH).
- Lipid peroxidation and mtDNA damage disable ETC complexes, increasing leak and ROS yield.
- ROS activate inflammatory cascades (NF-κB, PARP-1, and PKC), further depleting NAD⁺ and ATP.
This biochemical spiral matches the neuronal calcium-driven cycle seen in glutamate excitotoxicity.
Cortisol–Glutamate Convergence
Cortisol not only elevates glucose but also enhances excitatory neurotransmission:
- Presynaptic: Increases vesicular glutamate loading and release probability through VGLUT upregulation.
- Postsynaptic: Upregulates NMDA and AMPA receptor subunit transcription via NR3C1 binding to GREs.
- Glial: Downregulates EAAT2, slowing synaptic glutamate clearance.
Thus, both systemic hyperglycemia and synaptic hyperexcitability converge on the same target: mitochondrial overload.
Glucose floods mitochondria with substrate, while glutamate floods them with calcium.
Both inputs open the same oxidative pathway of ETC congestion, ROS overflow, and energetic failure.
Therapeutic Implications
The review highlights mitochondria-targeted antioxidants and metabolic stabilizers as interventions:
- MitoQ, SkQ1, SS-31, and Mito-TEMPO: Localize to the inner mitochondrial membrane to neutralize ROS at the source.
- Metformin: Mildly inhibits complex I, reducing electron pressure and ROS formation.
- SGLT2 inhibitors: Lower circulating glucose, indirectly reducing mitochondrial substrate overload.
In the neural context, these are paralleled by Riluzole or GABAergic agents, which reduce glutamatergic drive and preserve mitochondrial homeostasis.
Integration with Stress–Glutamate–ROS Model
| Stage | Diabetes Model | Stress–Glutamate–ROS Model |
|---|---|---|
| Upstream Driver | Hyperglycemia, insulin resistance | Cortisol → NR3C1 activation |
| Main Effector | Substrate overload on ETC | Calcium influx via NMDA/AMPA |
| Mitochondrial Impact | ΔΨm collapse, ROS generation | ΔΨm collapse, ROS generation |
| Feedback | mtDNA damage, inflammation | NR3C1 methylation, inflammation |
| Outcome | Cardiomyopathy, β-cell death | Neurodegeneration, ALS-like pathology |
Both conditions represent overexcitation of cellular metabolism beyond sustainable thresholds.
Conclusion
Diabetes, in mechanistic terms, represents peripheral excitotoxicity.
Cortisol’s dual effects of raising glucose systemically and glutamate synaptically, create a unified model of energy-driven cellular degeneration.
Mitochondria act as the convergence point where stress, metabolism, and excitatory signaling meet.
Therapeutic correction requires dampening both arms: reducing substrate overload and moderating excitatory throughput.
This framework bridges metabolic and neurodegenerative diseases under a single bioelectric–metabolic continuum.