Mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4 (MT-ND4)

MT-ND4 (Mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4) is a protein-coding gene located in the mitochondrial genome that encodes a key subunit of Complex I, the first enzyme of the mitochondrial respiratory chain (UniProt P03905). This subunit is essential for the process of oxidative phosphorylation, which generates the majority of cellular ATP required for the high metabolic demands of retinal ganglion cells (RGCs) (NCBI Gene ID: 4538). Mutations in the MT-ND4 gene, most notably the m.11778G>A transition, are the primary cause of Leber Hereditary Optic Neuropathy (LHON), a rare genetic disorder leading to bilateral central vision loss (NIH MedlinePlus). The mutation results in mitochondrial dysfunction and increased oxidative stress, specifically triggering the apoptosis of RGCs (Yu-Wai-Man et al., 2011). As a therapeutic target, MT-ND4 is the focus of gene therapy efforts like lenadogene nolparvovec (Lumevoq), which uses an adeno-associated virus (AAV2) to deliver a wild-type version of the gene to the nucleus of RGCs (EMA, 2023). This approach, known as allotopic expression, allows the functional protein to be synthesized in the cytoplasm and imported into the mitochondria to restore the electron transport chain and preserve vision (GenSight Biologics).

Other names

ND4MTND4NADH dehydrogenase subunit 4NADH-ubiquinone oxidoreductase chain 4Complex I subunit 4

Gene replacement therapy utilizing allotopic expression, where a wild-type MT-ND4 gene is delivered to the nucleus of retinal ganglion cells via an AAV2 vector, translated in the cytoplasm, and imported into the mitochondria to restore Complex I function (GenSight Biologics; EMA, 2023).