1.06 TICA Pathways & 7 Deaths

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Part I - The Symptoms Imagine that you work at the medical examiner's office for a major metropolitan city. As Chief Medical Offi cer, you investigate suspicious deaths and provide toxicology services for the county. Unfortunately, it's been a busy week. In the past five days, seven people have died, all with similar symptoms. It is your job to examine the data and determine the cause of death for these victims. The first was a 12-year-old girl. Her parents said that she was awake in the middle of the night complaining of a stuffy nose and sore throat. They gave her an extra strength Tylenol and sent her back to bed. At 7am the next morning, the parents discovered that the girl had collapsed on the bathroom floor. An ambulance rushed the girl to a nearby hospital, where she was pronounced dead. That same day, paramedics found the second victim unconscious on his kitchen floor after what they thought was an apparent heart attack. Sadly, the victim's brother and fiancée also collapsed later that night while the family gathered to morn his passing. Both had taken Tylenol to help them cope with their loss shortly before collapsing; neither survived. In the next four days, four other similar deaths were reported, all in the same neighborhood and all with similar symptoms. Are these seven deaths related? What is causing these people to die? It is your job to answer these questions before more deaths are reported. Symptoms exhibited by most patients: Dizziness Confusion Headache Shortness of breath/rapid breathing Vomiting Most deaths were very rapid, occurring within a few hours of symptoms. Explain whether or not you think these 7 deaths are related, and what questions you would ask the families of the victims.

respiration - because of the damaged mitochondria

Part II - Autopsy Report Immediate cause of death was hypoxia (suffocation or lack of oxygen). Tissue sections from heart, lung, kidney, and liver all show massive cell death. Staining with specific dyes showed major mitochondrial damage within the affected tissues. Oxygen levels in the patients' blood were approximately 110 mm Hg (normal range is 75 - 100 mm Hg). What cellular function was disrupted in these patients?

What stands out from this table is that the NAD+/NADH ratio is abnormal in the dead patients. Given the information on mitochondrial damage, this implicates the electron transport chain for failure to cycle NADH to NAD+.

Part III - Subcellular Metabolite Analysis Detailed analysis of the damaged cells showed that ATP levels in the mitochondria were very low. Levels of pyruvate and acetyl coenzyme A (CoA) were normal. You begin to suspect a malfunction of a specific cellular metabolic pathway and so you request a more detailed analysis of the sub-cellular components of the affected cells from the autopsy. The levels of key metabolites are reported below: In your groups, discuss the roles of each of these metabolites in cellular respiration, and whether they are substrates or products of which pathways. In LC, submit your answer to the following question: What cellular process or pathway is abnormal in these patients, based on these metabolite levels? glycolysis citric acid cycle electron transport chain pyruvate oxidation

it would decrease With no electron flow, no protons will be pumped across the inner mitochondrial membrane. The proton gradient that exists will quickly dissipate as protons return through the ATP synthase, until the proton concentrations are nearly the same on both sides of the membrane. ATP synthesis will slow as the proton gradient decreases, and stop completely when the proton gradient is too small.

Part IV - Role of Cyanide In the presence of cyanide, what would happen to the rate of ATP synthesis in the mitochondria? it would increase it would decrease it would stay the same

it would decrease With cytochrome c oxidase unable to transfer electrons to oxygen, the electrons would back up in the ETC, and electron flow will stop.

Part IV - Role of Cyanide You are now convinced that you know the cause of death for these victims and quickly report it back to the police as this is a very dangerous situation. After realizing that the electron transport chain was no longer functioning, you started to suspect poisoning and ran a blood test for various poisons that you knew affected the electron transport chain. The test of all seven patients came back positive for cyanide. Cyanide irreversibly binds to cytochrome c oxidase (CcOX) of the electron transport chain and prevents the transfer of electrons to oxygen, the final electron acceptor. In the presence of cyanide, what would happen to the flow of electrons down the electron transport chain (ETC)? it would increase it would decrease it would stay the same

it would decrease With no electron flow, no protons will be pumped across the inner mitochondrial membrane. The proton gradient that exists will quickly dissipate as protons return through the ATP synthase, until the proton concentrations are nearly the same on both sides of the membrane.

Part IV - Role of Cyanide You are now convinced that you know the cause of death for these victims and quickly report it back to the police as this is a very dangerous situation. After realizing that the electron transport chain was no longer functioning, you started to suspect poisoning and ran a blood test for various poisons that you knew affected the electron transport chain. The test of all seven patients came back positive for cyanide. Cyanide irreversibly binds to cytochrome c oxidase (CcOX) of the electron transport chain and prevents the transfer of electrons to oxygen, the final electron acceptor. In the presence of cyanide, what would happen to the proton gradient across the inner mitochondrial membrane? it would increase it would decrease it would stay the same

it would increase In the absence of mitochondrial function, one way for cells to make ATP is by substrate-level phosphorylation that occurs during glycolysis, coupled with a way to recycle NADH back to NAD+ via fermentation reactions.

Part V - Connections to other metabolic pathways In the presence of cyanide, but before the cell dies, what would happen to the rate of glycolysis? it would increase it would decrease it would stay the same

The citric acid cycle is located in the mitochondrial matrix. It reduces NAD+ (and FAD) to NADH (and FADH2). These reduced electron carriers then shuttle their electrons to the ETC, and become oxidized back to NAD+ (and FAD) to return to the citric acid cycle. With the ETC all backed up, NADH (and FADH2) have nowhere to dump their electrons, and can't cycle back to their oxidized forms. Without NAD+, the citric acid cycle stops.

Part V - Connections to other metabolic pathways In the presence of cyanide, how would the loss of electron transport chain (ETC) function affect the citric acid cycle? Explain where the citric acid cycle enzymes are located in a cell and how the citric acid cycle is connected to the ETC.

oxygen levels in the patients' blood at 110 mm Hg

What data in the autopsy seems inconsistent with hypoxia as the immediate cause of death? tissue sections showing massive cell death staining with dyes showing major mitochondrial damage oxygen levels in the patients' blood at 110 mm Hg