Use the following passage to answer questions: Mitochondria are thought to play a key regulatory role in the development of neurodegenerative disease and other age-related pathology. The organelle is the main source of ATP for the cell and is also involved in numerous processes, including phospholipid biosynthesis and calcium signaling. However, the process that forms ATP, termed oxidative phosphorylation, requires the transfer of electrons from food-derived molecules to oxygen and results in the production of reactive oxygen species (ROS). Indeed, most ROS are due to mitochondrial... Show more Use the following passage to answer questions: Mitochondria are thought to play a key regulatory role in the development of neurodegenerative disease and other age-related pathology. The organelle is the main source of ATP for the cell and is also involved in numerous processes, including phospholipid biosynthesis and calcium signaling. However, the process that forms ATP, termed oxidative phosphorylation, requires the transfer of electrons from food-derived molecules to oxygen and results in the production of reactive oxygen species (ROS). Indeed, most ROS are due to mitochondrial respiration. An estimated 1% to 2% of oxygen that is taken up by the body is turned into these radical species. Out of likely necessity, eukaryotic cells have evolved ample defense mechanisms to protect themselves from oxidative damage, including several mitochondrial antioxidant factors. Yet cellular insults can overcome the mechanisms for removing these species, resulting in a net gain in ROS. Oxidative stress can damage mitochondrial DNA (mtDNA), such as by causing double- and single-strand breaks, which are potentially mutagenic. Additional casualties of oxidative damage are mitochondrial proteins, some of which play important roles in the citric acid cycle upstream of oxidative phosphorylation and, thus, the generation of ATP. The depletion of ATP associated with ROS can lead to the induction of necrosis or to caspase-mediated apoptosis. Several lines of evidence suggest that mutations in mtDNA, which may result from oxidative stress, can cause age-related pathology. Mice that are genetically engineered to accumulate these mutations have phenotypes associated with early-onset aging: weight loss, alopecia, sarcopenia, and gonadal atrophy. Furthermore, analyses of the degenerated tissue in these animals revealed elevated levels of activated caspase enzymes that are markers for apoptosis. There is also mounting evidence that oxidative damage, as well as defenses against such damage, is associated with aging. Transcriptional analysis of postmortem brain samples from individuals ranging from ages 26 to 106 revealed, starting at around age 40, a decrease in expression of genes involved in mitochondrial function and an increase in stress-response, antioxidant, and DNA repair genes. Beyond normal aging, mitochondrial mutations and oxidative stress have been implicated in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. Experimental damage to the mitochondria is associated with Alzheimer's-like pathology in cells in vitro, such as increased amyloid-β peptide levels, and in animal models. A transgenic mouse that is deficient in the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) developed amyloid-β plaques in the brain. Moreover, a number of disease-associated proteins, such as amyloid-β, amyloid precursor protein (APP), and parkin, which is associated with Parkinson's disease, have been found to interact with the mitochondria. However, these lines of evidence raise many new questions. For example, it is unclear why certain tissues are affected by mitochondrial mutations more than others, although it has been speculated that those with the highest energy demand are also the most susceptible to genetic aberrations. Furthermore, many questions remain about the potential of antioxidant treatment to affect the prognosis of age-related pathology. Thus far, clinical trials in which one or several antioxidants are given have reported little benefit. It remains possible that a more complex strategy for antioxidant therapy would be more beneficial. Show less
Use the following passage to answer questions:
Mitochondria are thought to play a key regulatory role in the development of neurodegenerative disease and other age-related pathology. The organelle is the main source of ATP for the cell and is also involved in numerous processes, including phospholipid biosynthesis and calcium signaling. However, the process that forms ATP, termed oxidative phosphorylation, requires the transfer of electrons from food-derived molecules to oxygen and results in the production of reactive oxygen species (ROS). Indeed, most ROS are due to mitochondrial respiration.
An estimated 1% to 2% of oxygen that is taken up by the body is turned into these radical species. Out of likely necessity, eukaryotic cells have evolved ample defense mechanisms to protect themselves from oxidative damage, including several mitochondrial antioxidant factors. Yet cellular insults can overcome the mechanisms for removing these species, resulting in a net gain in ROS. Oxidative stress can damage mitochondrial DNA (mtDNA), such as by causing double- and single-strand breaks, which are potentially mutagenic.
Additional casualties of oxidative damage are mitochondrial proteins, some of which play important roles in the citric acid cycle upstream of oxidative phosphorylation and, thus, the generation of ATP. The depletion of ATP associated with ROS can lead to the induction of necrosis or to caspase-mediated apoptosis. Several lines of evidence suggest that mutations in mtDNA, which may result from oxidative stress, can cause age-related pathology. Mice that are genetically engineered to accumulate these mutations have phenotypes associated with early-onset aging: weight loss, alopecia, sarcopenia, and gonadal atrophy. Furthermore, analyses of the degenerated tissue in these animals revealed elevated levels of activated caspase enzymes that are markers for apoptosis. There is also mounting evidence that oxidative damage, as well as defenses against such damage, is associated with aging.
Transcriptional analysis of postmortem brain samples from individuals ranging from ages 26 to 106 revealed, starting at around age 40, a decrease in expression of genes involved in mitochondrial function and an increase in stress-response, antioxidant, and DNA repair genes. Beyond normal aging, mitochondrial mutations and oxidative stress have been implicated in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. Experimental damage to the mitochondria is associated with Alzheimer's-like pathology in cells in vitro, such as increased amyloid-β peptide levels, and in animal models. A transgenic mouse that is deficient in the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) developed amyloid-β plaques in the brain.
Moreover, a number of disease-associated proteins, such as amyloid-β, amyloid precursor protein (APP), and parkin, which is associated with Parkinson's disease, have been found to interact with the mitochondria. However, these lines of evidence raise many new questions. For example, it is unclear why certain tissues are affected by mitochondrial mutations more than others, although it has been speculated that those with the highest energy demand are also the most susceptible to genetic aberrations. Furthermore, many questions remain about the potential of antioxidant treatment to affect the prognosis of age-related pathology. Thus far, clinical trials in which one or several antioxidants are given have reported little benefit. It remains possible that a more complex strategy for antioxidant therapy would be more beneficial.
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