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NBME 23 Answers

nbme23/Block 2/Question#4

An 18-year-old woman comes to the physician because ...

Maximum oxygen consumption (VO2max): decreased;
Venous blood lactate: increased;
Energy production by glycolysis: increased

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The question stem is describing a mitochondrial disease, which commonly present with lactic acidosis. There is an increase in anaerobic forms of energy production (glycolysis). The mitochondria are faulty, so they can’t use the end product of glycolysis (pyruvate) in TCA. Instead pyruvate is shunted over and is used by LDH (lactate dehydrogenase) to generate pyruvate.

Aside: Recall that LDH uses NADH and generates NAD+. Deficiency of LDH can lead to loss of regeneration of NAD+ and inhibits glycolysis.

drdoom  ... pyruvate is shunted over and is used by LDH (lactate dehydrogenase) to generate lactate*. +  
chris07  It's hinted in the answer, but I would like to clarify: max O2 consumption is decreased because O2 is consumed in the Electron Transport Chain, which occurs in the mitochondria. With the mitochondria not working, the ETC cannot work, and thus there is less demand for Oxygen. +8  
masonkingcobra  Mitochondria are the powerhouse of the cell +18  
uslme123  Apparently ragged red fibers are the result of coarse subsarcolemmal or intermyofibrillar mitochondrial accumulations.. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/mitochondrial-myopathy +  

 +3  upvote downvote
submitted by soph(23),

pt with progressive muscle weakness--> resp muscles not working --> decrease oxygen consumption. no oxygen= no aerobic metabolism --> increase venous lactate, also you keep doing anaerobic glycolysis since you cant go to TCA --> increase energy production via glycolysis :)

 +2  upvote downvote
submitted by nwinkelmann(137),

So this question was something I really struggled with. I didn't recognize that the presentation was of MERRF as someone stated below, and I know you don't need to know that to answer the question, but it would have been helpful. My biggest frustration was the wording of the biopsy results "abnormal accumulations of mitochondria." This annoyed me because the definition of ragged red fibers (which I'm assuming was their intention) is "accumulations of abnormal mitochondria." Those are two very different statements in my mind, lol. The first, to me, just means there's too much mitochondria, but the second means there's too much AND they aren't functioning properly. It's also just the fact of remembering all of the terms for ETC at the time of reading the question (i.e. I didn't think about the fact that ETC is also called cellular respiraton or just respiration).

I also didn't really understand fully what VO2max is = "VO2 max, also known as maximal oxygen uptake, is the measurement of the maximum amount of oxygen a person can utilize during intense exercise... and is based on the premise that the more oxygen consumed during exercise, the more the body will generate adenosine triphosphate (ATP) energy in cells... VO2 max is reached when your oxygen consumption remains at a steady state despite an increase in the workload. It is at this plateau that the [muscle] moves from aerobic metabolism to anaerobic metabolism" https://www.verywellfit.com/what-is-vo2-max-3120097.

Based purely on this definition, where VO2max = essentially the time at which aerobic switches to anaerobic respiration, my interpretation of too much mitochondria vs too much and bad mitochrondria didn't matter, because even when the mitochondria are functioning properly, they reach a point and switch to anaerobic, thus if there was too much normal mitochondria, this would occur faster because there would be more overall cellular respiration occuring, meaning the body would switch to anaerobic and utilize glycolisis to lactate for energy, stop utilizing the mitochondria, and thus VO2max would decrease.

HOWEVER.... because this is a MERRF question, the order of events is a little different, despite the outcome being the same (at least that's how I understand it). So, I think the key to any mitochondrial disorder is remembering that the mutations are almost certainly going to affect an encoded protein and thus a deficiency of that protein. One article that I found said that the tRNA mutations (as in MERRF) cause: "disrupt mitochondrial protein synthesis, decreasing the activity of Complex I and to a lesser extent Complex IV... which decreases respiration and lowers proton pumping, dramatically decreasing the membrane potential and proton electrochemical potential gradient across the mitochondrial inner membrane. The proton electrochemical potential gradient is the driving force for ATP synthesis and decreasing it substantially lowers the maximal rate of ATP synthesis." https://febs.onlinelibrary.wiley.com/doi/full/10.1046/j.1432-1327.1999.00066.x

Based on my understanding of oxidative phosphorylation, O2 consumption (i.e. taking the electron from complex IV and putting it on 1/2 O2 to create H2O and H+ drives the proton gradient which drives ATP production. Thus: deficient respiratory oxidation (i.e. mtDNA mutations of the ETC enzymes) leads to lowered O2 consumption (so lowered VO2 max) which then leads to lowered ATP production, and thus defective mitochondria. Then, lowered mitochondrial function leads to decreased aerobic respiration shunting ATP production to anaerobic respiration, driven by glycolysis, and thus increasing lactate levels.

Hope this helps! This took me WAY TOO LONG to figure out, lol, but hopefully I never freaking forget it, lol.

Also, if you want any more reading, I finally found an article that actually fully explains the biochemical and pathophysiology of mitochondrial myopathies: https://academic.oup.com/brain/article/126/2/413/332457

Sorry it's so long!

djtallahassee  lol yea. I thought they were trying to say there was an abnormally large amount of mitochondria present which made me get the opposite answer :/ +  

 +0  upvote downvote
submitted by diabetes(4),

can somebody explain how energy production by glycolysis increased, since aerobic glycolysis produce 32 net ATP,compare to 2 net ATP through anaerobic glycolysis ?

diabetes  i think the stem should be "energy production by an anaerobic glycolysis " +1  
blueberrymuffinbabey  yeah that's the bit that tripped me up too. i get that there would be increased glycolysis in general to compensate for lack of TCA function but...the fact that it says "energy production by glycolysis" is kind of misleading/confusing. +