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Figure 3 | Nutrition & Metabolism

Figure 3

From: Mitochondrial-associated metabolic disorders: foundations, pathologies and recent progress

Figure 3

Mutations affecting oxidative phosphorylation are the foundation of mitochondrial-associated metabolic disorders. Mutations (red) in genes critical for mitochondrial processes (green) lead to mitochondrial-associated diseases (blue). Human mtDNA encodes 13 proteins (including subunits of ETC complexes) and 22 tRNAs on a circular genome. A D-loop region is the site of mtDNA polymerase gamma binding. Mutations within the D-loop region, or in the POLG gene, lead to defects in mtDNA replication and eventually mtDNA depletion. In the case of MNGIE, mutations in the nuclear TYMP gene, which encodes a protein involved in nucleotide synthesis, also lead to defects in mtDNA replication due to an unbalanced nucleotide pool. Mitochondria that have no mtDNA copies can no longer synthesize ETC subunits encoded by the mtDNA, leading to defects in oxidative phosphorylation. In another example of a mutation in a nuclear gene affecting mitochondrial function, mutations in genes encoding proteins required for CoQ synthesis lead to CoQ deficiency and therefore defects in electron transfer in the ETC, resulting in defects in oxidative phosphorylation. Finally, mutations in mtDNA genes themselves, including genes encoding ETC subunits or tRNAs essential for mitochondrial gene expression, lead to defects in the synthesis of ETC protein subunits or non-functional complexes. Such mutations comprise the majority of mutations associated with mitochondrial-associated diseases (excluding POLG mutations), and have been associated with lactic acidosis, MELAS, and mitochondrial myopathies.

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