The malate aspartate shuttle and the glycerol 3-phosphate shuttle are two mechanisms involved in the inner mitochondrial membrane. Dihydroxyacetone phosphate (DHAP), dinucleotide (NAD(H)), and coenzyme Q (CoQ) play important roles in these processes.

Defects in oxidative phosphorylation, which is the process responsible for ATP production, can be caused by mutations in mtDNA. About 13 out of the approximately 90 polypeptides required for oxidative phosphorylation are encoded by mtDNA and synthesized within the mitochondria. The remaining proteins are encoded by nuclear DNA, synthesized in the cytosol, and then transported into the mitochondria. It is worth noting that mtDNA has a higher mutation rate compared to nuclear DNA. Tissues with high ATP requirements, such as the central nervous system, skeletal and heart muscles, and the liver, are most affected by these defects. Some diseases, including mitochondrial myopathies and Leber hereditary optic neuropathy, are associated with mutations in mtDNA. In Leber hereditary optic neuropathy, bilateral loss of central vision occurs due to neuroretinal degeneration and damage to the optic nerve. It is important to mention that mtDNA is inherited maternally, as mitochondria from the sperm cell do not enter the fertilized egg.

Mitochondria also play a role in the process of apoptosis, which is programmed cell death. The intrinsic (mitochondrial-mediated) pathway of apoptosis involves the formation of pores in the outer mitochondrial membrane. These pores allow cytochrome c to be released from the intermembrane space and enter the cytosol. Once in the cytosol, cytochrome c, together with proapoptotic factors, activates a family of proteolytic enzymes called caspases. The activation of caspases leads to the cleavage of key proteins, resulting in the characteristic morphological and biochemical changes observed during apoptosis.

In summary, defects in oxidative phosphorylation can arise from mutations in mtDNA, particularly affecting tissues with high ATP demands. Additionally, mitochondria are involved in the intrinsic pathway of apoptosis, where pores in the outer mitochondrial membrane allow the release of cytochrome c and activation of caspases.
inner mitochondrial membrane. A. Glycerol 3-phosphate shuttle. B. Malate aspartate shuttle. DHAP = dihydroxyacetone phosphate; NAD(H) = dinucleotide; CoQ = coenzyme Q.
C. Inherited defects in oxidative phosphorylation
Thirteen of the ~90 polypeptides required for oxidative phosphorylation are encoded by mtDNA and synthesized in mitochondria, whereas the remaining proteins are encoded by nuclear DNA, synthesized in the cytosol, and then transported into mitochondria. Defects in oxidative phosphorylation are more likely a result of alterations in mtDNA, which has a mutation rate about 10 times greater than that of nuclear DNA. Tissues with the greatest ATP requirement (for example, the central nervous system, skeletal and heart muscle, and the liver) are most affected by defects in oxidative phosphorylation. Mutations in mtDNA are responsible for several diseases, including some cases of mitochondrial myopathies, and Leber hereditary optic neuropathy, a disease in which bilateral loss of central vision occurs as a result of neuroretinal degeneration, including damage to the optic nerve. [Note: mtDNA is maternally inherited because mitochondria from the sperm cell do not enter the fertilized egg.]
D. Mitochondria and apoptosis
The process of apoptosis (programmed cell death) may be initiated through the intrinsic (mitochondrial-mediated) pathway by the formation of pores in the outer mitochondrial membrane. These pores allow cytochrome c to leave the intermembrane space and enter the cytosol. There, cytochrome c, in association with proapoptotic factors, activates a family of proteolytic enzymes (the caspases), causing cleavage of key proteins and resulting in the morphologic and biochemical changes characteristic of apoptosis.
VII. CHAPTER SUMMARY