Energy Metabolism 4: ATP Synthase and Uncoupling 2021 PDF

Bioenergetics: ATP synthesis and uncoupling This Photo by Unknown Author is licensed under CC BY-SA  ATP synthesis This Photo by Unknown Author is licensed under CC BY-NC-ND Th...

Bioenergetics: ATP synthesis and uncoupling This Photo by Unknown Author is licensed under CC BY-SA  ATP synthesis This Photo by Unknown Author is licensed under CC BY-NC-ND This Photo by Unknown Author is licensed under CC BY-NC-ND  ATP synthas e This Photo by Unknown Author is licensed under CC BY-NC-ND  Protons cannot pass back through the inner mitochondrial membrane on their own so they are trapped in the intermembrane space. This is because the core of any bilayer membrane is too hydrophobic for ions to get through in large amounts. They need help. Help comes in the form of ATP synthase, also called complex 5. the formation of ATP from ASDP is energetically unfavourable ie it requires energy input to add on the phosphate group to ADP. ATP synthase harnesses the energy from the proton gradient to drive the synthesis. It consists of two subunits, FO and F1. F1 can rotate in relation to FO, which anchors it in the membrane. This ability to rotate means it is a molecular machine or turbine. Protons move through a channel in FO and bind to a ring on FO. This binding causes Fo to rotate a notch. The H+ ions can then exit from FO into the lumen. This is like a one way revolving door. The torque is transferred to the F1 subunit by a central stalk that connects the two subunits. The stalk is not circular but shaped like a cam shaft so as it rotates, it squashes the f1 subunit and causes a conformational change in F1. F1 is made of 3 dimers arranged in a ring. First, the ADP and P1 bind in the gap between two dimers, then a rotation of the stalk causes the dimers to squash together, this squashes ADP and Pi together and makes them fuse to form ATP. Another rotation of the stalk (remember this is driven by the H+ movement through FO) lets the dimers pop apart again, releasing the newly formed ATP and allowing ADP and Pi to bind again. A flexible peripheral stalk holds the two subunits together and allows the dimers to flex with each rotation of the internal stalk. ATP synthase actually dimerises, which gives the inner mitochondrial membrane its characteristic folds called christae. This process means the proton gradient is foucssed near ATP synthase and makes the process highly efficient.  Watch it work https://youtu.be/b_cp8MsnZFA  The PROTON gradient couples OXIDATION (of fuels by ETC) to PHOSPHORLATION (of ADP by ATP synthase) The protonmotive force The important thing to remember is that the proton gradient couples oxidation of fuels to phosphorylation of ADP to produce chemical energy in the form of ATP, and this is called the proton motive force. Other uses of the proton gradient The proton motive force can also be sued for active transport including driving entry of pyruvate into the mitochondria, entry of ADP and exit of ATP so it can be used by cytoplasmic enzymes. Movement  In prokaryotes, the complexes I have described here are not encased in mitochondria. They can set up a proton pump between the cytoplasm and the intermembrane space between the outer bacterial membrane and the inner one, much like in a mitochondrion. They can use the flow of protons to drive flagella movement. This is very reminiscent of how the proton gradient is used to drive the motor of the FO and F1 in ATP synthase, except here, instead of making ATP, the energy is directed into movement, or kinetic energy  Making heat BAT= brown adipose tissue: highly vascularised ;lots of mitochondria for heat production WAT: white adipose tissue: few mitochondria and specialised for fat storage H+ ETC ATP made H+ ATP NOT made Energy dissipates as HEAT UCP1 = UCP1 uncoupli ng protein  Remember that the electron transfer chain results in a build up of protons in the intermembrane space in mitochondria. The head of protons is used to drive ATP synthesis through ATP synthase. Normally, there is some ‘proton leak’ across the membrane which dissipates energy as heat. This is quite minor but nevertheless helps endotherms to generate their own body heat: reptiles have much lower background proton leak than mammals and birds. However, in BAT we also have UCP1, a protein, that when activated allows the protons to move back rapidly and generate heat rather than ATP. It’s a great fast track method for maintaining body temperature when you get cold. Obviously, if all your cells did this, you would die from lack of ATP. So the process is done in specialised cells and it is carefully regulated so that the cells don’t flatline (ie lose their ATP generating capacity altogether). It used to be believed that only newborns had significant BAT depots between their shoulder blades that they used to regulate temperature shortly after birth when small and when other aspects of thermal balance were developing. However, back in 2009, scientists investigating an unusual form of cancer called a ‘hibernoma’ were using a kind of whole-body imaging to find the tumours that identifies regions of high glucose uptake. What they discovered was that people without the cancers had lots of little diffuse ‘bright spot’ throughout their fat tissue. Yes, they found that adult humans actually do have BAT but its harder to find than in babies because the depots are small, scattered, not predictable in location between people and only activate when the person is cold. The most predictable location is under the clavicles in the neck. You can imagine how this revelation was received, and the idea that WAT could be ‘browned up’ to help people lose fat mass has gained lots of traction. Is uncoupling a way to lose weight? This Photo by Unknown Author is licensed under CC BY-NC  In the 1930s a chemical called dintrophenol or DNP was marketed as a powerful weight loss drug. It works by uncoupling the electron transfer chain from ATP synthesis by collapsing the proton gradient in an uncontrolled way. Serious side effects such as hyperthermia result because the energy normally used to drive ATP production is dissipated as heat. The inability to control this process means that cells can no longer produce enough energy and at the same time generate too much heat. The drug is no longer legally sold but it can still be purchased illegally and people die as a result of uncontrolled uncoupling of oxidation from phosphorylation.