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Following endocytosis, the HoloTC complex is degraded in lysosomes and free B12 is released into the cytoplasm, via CblF (Rutsch et al., 2009) and CblJ ( This free cytoplasmic B12 undergoes a series of intracellular transport and modifications to enable two core enzymatic reactions: 1) adenosyl-B12 acts as a co-factor for the enzyme methylmalonyl-coA mutase that catalyzes the conversion of methylmalonyl-coA to succinyl-coA, thereby enabling restoration of tricarboxylic acid (TCA) cycle intermediates and 2) methyl-B12 enables methionine synthase in the re-methylation of homocysteine to methionine using methyl-tetrahydrofolate (MTHF) as a methyl donor, thereby enabling the vital biochemical pathways of the folate cycle and methionine cycle, facilitating the downstream synthesis of important compounds like DNA and RNA (Figure 2)

Specifically, a total of 11 sites have been proven to generate ROS in the ETC, a finding which has been reviewed elsewhere (47, 48)

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