Summary
This narrative review challenges the conventional oxidative stress paradigm by proposing that reductive stress—an accumulation of reducing equivalents (NADH/NADPH)—may be equally important in driving mitochondrial dysfunction and chronic disease. The authors argue that a hyper-reduced mitochondrial environment paradoxically increases ROS generation through electron leakage, and identify chronic hyperglycaemia, high-fat diets, and polyunsaturated omega-6 enrichment as key drivers of reductive overload. The review proposes refined redox assessment methods and therapeutic interventions targeting NAD+ restoration and electron transport chain optimisation.
Regional applicability
The mechanistic insights on mitochondrial redox dysregulation and dietary contributions to reductive stress are relevant to United Kingdom populations given high prevalence of type 2 diabetes, fatty liver disease, and metabolic syndrome. However, as a biochemical mechanisms review without population-specific data, direct applicability to UK clinical practice and policy would require integration with evidence from UK cohorts and dietary contexts.
Key measures
Redox biomarkers including lactate:pyruvate and β-hydroxybutyrate:acetoacetate ratios; NADH and NADPH concentrations; mitochondrial electron transport chain flux; ROS generation
Outcomes reported
This narrative review synthesises evidence on reductive stress (elevated NADH/NADPH) as a driver of mitochondrial dysfunction and chronic diseases including type 2 diabetes, nonalcoholic fatty liver disease, and neurodegeneration. It examines dietary and metabolic factors contributing to reductive overload and proposes redox biomarkers and therapeutic strategies to restore mitochondrial redox balance.
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