Ketogenic diet in treating NADH accumulation caused by complex I dysfunction: the metabolic wisdom of "dredging, not repairing".

Genetic mutations causing Complex I (CI) dysfunction lead to the accumulation of NADH in the mitochondrial matrix due to impaired oxidation. An elevated NADH/NAD⁺ ratio feedback-inhibits key enzymes of the tricarboxylic acid (TCA) cycle, reducing metabolic flux, while concurrent electron transport chain (ETC) blockade exacerbates reactive oxygen species (ROS) generation and oxidative stress. Conventional views propose that the ketogenic diet (KD) bypasses the defective CI to restore downstream ETC electron transfer. However, this perspective harbors an inherent contradiction: CI is the primary entry point for NADH oxidation; bypassing it may sustain some electron flow but fails to consume the accumulated NADH in the matrix, leaving the fate of this critical reducing equivalent inadequately explained. This article proposes the metabolic wisdom of "dredging, not repairing", positing that KD, through metabolic reprogramming, diverts the accumulated NADH into multiple utilizable pathways. These include intra-matrix conversion and consumption (generating NADPH and ketone bodies), pumping malate from the matrix into the cytosol via the reverse malate-aspartate shuttle (rMAS), and further cytosolic malate utilization (gluconeogenesis, NADPH generation, glycerol-3-phosphate shuttle, etc.). This multi-pathway synergy achieves "dredging"rather than "repair". This paper aims to elucidate how KD, via metabolic reprogramming, alleviates the inhibition of the TCA cycle caused by NADH accumulation and restores its flux, thereby offering new insights into metabolic therapeutic strategies for CI-deficient mitochondrial diseases.