Fig. 7.

Scheme illustrating MDH2 deficiency (MDH2D) and selected effects of triheptanoin. MDH2 is located in the mitochondria and is part of the TCA cycle and the malate-aspartate shuttle (MAS). MDH2 as part of the MAS is required for the transfer of NADH generated in the cytosol into the mitochondria. MDH2 as part of the TCA cycle converts malate into oxaloacetate thereby generating (intramitochondrial) NADH (not shown). In MDH2D (illustrated as a blue cross through the MDH2 enzyme) cytosolic NADH cannot be transferred into the mitochondria and less NADH is generated intramitochondrially. As a consequence, NADH is accumulating in the cytosol. One cellular adaptation in MDH2D is a compensatory and increased conversion of pyruvate into lactate in order to re-oxidize cytosolic NADH into NAD⁺. Triheptanoin has several potential modes of action (for details see discussion). Here, we schematically illustrate the breakdown of triheptanoin into glycerol and C7 fatty acid. While glycerol has several mechanisms of action (not illustrated here), C7 enters the mitochondria directly and is degraded in the beta-oxidation to C2 and C3 thereby enhancing the intramitochondrial NADH generation. C2 and C3 are anaplerotic by entering the TCA cycle.