Final Quiz

Aerobic respiration

Occurs in the mitochondrion in eukaryotes. Occurs in two major steps: Tricarboxylic acid (TCA) cycle and Oxidative phosphorylation (OXPHOS)

TCA cycle

Generates NADH and another reduced coenzyme FADH2, consumes water and yields CO2 as a byproduct.

Coenzyme A

CoA is a shuttle for acetyl groups. Functions : entry point into aerobic respiration, product of fat oxidation, substrate for fat synthesis

TCA Cycle entry

Pyruvate is oxidized and two of its three carbons are linked to Coenzyme A, yielding 1 NADH, 1 CO2 and acetyl CoA. Acetyl CoA donates these two carbons to oxaloacetate with the hydrolysis of water to yield citrate.

TCA cycle : NADH and ATP generation

Subsequent steps oxidize the molecule to yield NADH and at one point, GTP. The GTP may or may not be used to generate ATP. More CO2 is generated.

TCA cycle : FAD and completing the cycle

FAD is used as an electron acceptor at one point in the cycle, yielding FADH2. With the reduction of one last NAD+ in the next step, we once again have oxaloacetate ready to accept a new acetyl group from acetyl CoA

FAD

FAD is the oxidized form while FADH2 is the reduced form.

TCA cycle : the complete reaction

Net yield per glucose : 4ATP, 10 NADH and 2 FADH2. NADH and FADH2 are used to make more ATP via oxidative phosphorylation

Electron transport system : respiratory complexes

Uses the transfer of electrons from NADH/FADH2 to drive the transmembrane transport of protons up their concentration gradient.

FADH2 oxidation

Moves fewer protons. A result of passing electrons to respiratory complex II instead of complex I. 4 fewer protons moved.

F1F0 ATP synthase

ATP can power rotation of the stalk within F1. In the cell, 3 protons flowing through F0 rotate the stalk 120 degrees and drive the synthesis of 1 ATP from ADP

Overview of Oxidative Phosphorylation

Each NADH drives the transport of 10 H+ across the inner membrane. Each FADH2 drives the transport of 6H across the inner membrane. Synthesis of 1 ATP by F1 requires flow of 3H+ back through F0. Per glucose \~ 34 ATP are generated.

Complete overview

Yield from 1 glucose : 2 ATP from glycolytic pathway, 2 ATP from the TCA cycle, 30 ATP from oxidative phosphorylation via 10 NADH, 4 ATP from oxidative phosphorylation via 2 FADH2 = 38 ATP

Transport

The inner membrane is impermeable to large or polar species, just like any lipid bilayer. The mitochondrion provides transporters for species such as ATP, ADP, pyruvate, water and pi

Amino acids

Reactions permit conversions of some amino acids into pyruvate or elements of the TCA cycle. Permits the catabolism (breakdown) or anabolism (synthesis) of amino acids

Beta oxidation of fats

A series of oxidation reactions allows CoA to be linked to the carboxyl group on fatty acids. Cleavage at the Beta carbon yields acetyl- CoA which feeds directly into TCA. The process also yields NADH and FADH2.

Low fat diet doesn’t work, why?

Fats can still be synthesized via glycerol and acetyl CoA.

Starvation diet

A person on a low carb/low protein diet will use oxaloacetate for gluconeogensis. Oxaloacetate can be produced from certain amino acids which leads to muscle wasting. Acetyl-CoA from fatty acid breakdown will need to be disposed of by formation of ketones.

High protein, low carb diet

Amino acids from the diet provide the oxaloacetate. Acetyl CoA and glycerol are provided from breakdown of fats.

Lifestyle change

Balanced calorie diet combined with exercise. Both of which contribute to lipolysis via lessened fat burden from dietary sources and increased oxidative capacity which metabolize fat.

Why alcohol leads to fat accumulation

Alcohol is oxidized to acetaldehyde by reverse action of alcohol dehydrogenase using NAD+. Acetaldehyde may be metabolized to acetyl CoA by acetaldehyde dehydrogenase using another NAD +.

Toxicity of acetaldehyde

Causes mitochondrial failure, increasing generation of free radicals, depletion of anti-oxidants, like glutathione, formation of acetaldehyde adducts yielding neoantigens. Triggers collagen secretion

Hallmarks of cirrhosis

Accumulation of fat in hepatocytes, death of cells, immune attack and synthesis of collagen.

Intermittent fasting

Glycogen depletion in the liver occurs \~12-16 hours, triggering gluconeogenesis and then fat/protein catabolism after oxaloacetate depletion. Eating carbs after is largely dedicated to restoring the depleted metabolic intermediates and regaining glycogen stores in the liver.

Fasting beyond 12-16 hour window triggers what?

A mild state of ketosis and an elevate sensitivity to insuling.

Oxidative stress

An imbalance between the production of oxidizing compounds and a biological system’s ability to detoxify the reactive intermediates or repair the resulting damage.

Oxidizing Compounds

Reactive Oxygen Species (ROS) : superoxide and peroxide. Reactive Nitrogen Species (RNA) : nitric oxide and peroxynitrite

What constantly generates reactive oxygen species?

Aerobic metabolism

Electron transport system : respiratory complexes

uses the transfer of electrons from NADH/FADH2 to drive the transmembrane transport of protons up their concentration gradient

Superoxide production in Complex I

Free electrons leak from reduced FMN. Similar electron leakage can happen with Complex III

When molecules go bad, what happens?

Super oxide carbonylates proteins as well as reacting with other reactive compounds to make something worse. DNA is also damaged by reactive oxygen species.

How to mitigate the affects of ROS?

Scavenger enzymes, and Glutathione (GSH) which is an “antioxidant”

The effects of oxidative stress depends on what?

Light, pH, ions, metals, gasses, and other compounds