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  • Defects in mitochondrial oxidative phosphorylation (OXPHOS) frequently manifest with neuro-ophthalmologic symptoms. Acute-onset, bilateral, optic atrophy is the primary clinical sign of Leber hereditary optic neuropathy (LHON), which is caused by missense mutations in the mitochondrial DNA (mtDNA). Retinitis pigmentosa, frequently in association with Leigh syndrome, can be caused by mtDNA base substitutions, as well as by nuclear DNA (nDNA) OXPHOS gene mutations. Ophthalmoplegia and ptosis, together with mitochondrial myopathy, are associated with chronic progressive external ophthalmoplegia (CPEO) and the Kearns-Sayre syndrome (KSS), and can be caused by mtDNA rearrangements, nDNA mutations that destabilize the mtDNA, or mtDNA base substitutions. To understand the biochemical and molecular bases of mitochondrial neuro-ophthalmologic disease, it is necessary to understand the biochemistry and genetics of the mitochondrion, and the association between mitochondrial gene mutations and clinical symptoms.

  • Mitochondrial OXPHOS participates in three major cellular functions relevant to the pathophysiology of mitochondrial disease. First, the mitochondria generate much of the energy of the cell and this process regulates cellular redox potential, mitochondrial membrane potential, ATP production, and Ca++ uptake. Second, the mitochondria generate most of the endogenous reactive oxygen species (ROS) as a toxic byproduct of OXPHOS. Third, the mitochondria integrate many of the signals for initiating apoptosis through regulating the opening of the mitochondrial permeability transition pore (mtPTP). Opening of the mtPTP results in the release of cytochrome c and apoptotic enzymes from the mitochondrial intermembrane space, precipitating programmed cell death. All three of these processes use common OXPHOS polypeptides and functions.

    The OXPHOS complexes are composed of multiple polypeptides distributed between the mtDNA and nDNA. Complex I has 43 polypeptides, 7 (ND1, 2, 3, 4, 4L, 5, 6) from the mtDNA. Complex II has four nDNA subunits. Complex III has 11 subunits, 1 (CYTB) from the mtDNA. Complex IV has 13 polypeptides, 3 (COI, COII, COIII) from the mtDNA; and complex V has 16 polypeptides, 2 (ATP6, 8) from the mtDNA. In addition, the mtDNA encodes the 12S and 16S rRNAs and the 22 RNAs necessary for mitochondrial protein synthesis. The nDNA codes for all of the remaining OXPHOS complex subunits as well as the proteins necessary for their expression and assembly. The nDNA also codes for the mitochondrial inner membrane anion carriers, including the adenine nucleotide translocator (ANT), which exchanges mitochondrial ATP for cytosolic ADP; the mitochondrial Mn superoxide dismutase (MnSOD) and glutathione peroxidase (GPx1), which are involved in detoxifying mitochondrial ROS; and for proteins that constitute the mtPTP, including the ANT, the voltage-dependent anion channels (VDAC), the proapoptotic BAX family, the antiapoptotic BCL2 family, and cyclophilin D. The mechanisms for electron transport and proton pumping of each of the OXPHOS complexes are rapidly being elucidated, and this is permitting a detailed physiological understanding of some of the mitochondrial disease mutants. For example, the ATP synthases (complex V) are composed of a fixed component, the stator, which projects from the membrane into the matrix and is composed of the barrel of 3 α ...

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