Course:EOSC311/2020/Mitochondrial Function in the Tibetan Plateau

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Statement of Connection to Human Kinetics

This assignment connects my major of human kinetics to EOSC 311 by looking at the affect’s altitude has on overall mitochondrial function when individuals live or visit regions of great altitude such as the Tibetan Plateau. Within the field of human kinetics, a lot of valuable information has been learned about the functional anatomy of the human body by research done in places such as this. The Tibetan Plateau and its historic formation have created a unique landscape full of distinct terrain and climates that allows extensive research to take place. The article that inspired this project was written based off the findings from a large research expedition taking place in the Plateau[1]. Researchers were able to utilize the extreme geography to gain new insight into the functioning of human life. This project aims to provide a bridge between distinctly different fields and show the relevance between them.

The Tibetan Plateau

Figure 1.1. the Tibetan Plateau

The Tibetan Plateau is part of the Himalayan alpine system which extends from the Mediterranean Sea to the Sumatra Arc of Indonesia. The Plateau stretches over 1000 km north/south, and 2500 km east/west creating a surface area of 643 801 km2 [2]. The Plateau has an average elevation of over 5000m and is home to the two highest summits in the world, Mount Everest at (8848 m) and K2 at (8611m)[2][3][4]. This region experiences extreme differences in climate between the peaks and the plains. This extreme elevation was created approximately 70-80 million years ago (Ma) by a large collision between tectonic plates [5][2][6].

Plate Tectonic Movement

Figure 2.1. plate movement resulting in the movement of India towards Asia *note: Tethys Ocean is labelled as the later Indian Ocean*

Approximately 299 Ma one super continent named Pangea contained almost all land mass on earth. Starting around 200 Ma, the large land mass began to separate into the continents we see today[7]. This continental movement was made possible by tectonic plates. Tectonic plates are large fragments of the earth’s surface, lithosphere, that are constantly moving and interacting with one another. Plates are able to move as they are floating on a layer of weak rock, asthenosphere, that deforms as the plates moves [7]. The movement of plates determines the location of mountain belts, volcanoes, earthquakes, and the size and shape of the oceans and continents.

Following separation from Pangea, 225 Ma, India was part of a larger continent containing Antarctica and Australia, which was separated from today’s Asia by the former Tethys Ocean. As the large island moved away from Africa, the Indian ocean opened around 180 Ma. As the plate continued to move, India separated from Antarctica and Australia approximately 40 million yeas later. India now 6400 km south of Asia, moving north at a rate of 6-19 cm/year[5][6][7]. India continued towards Asia until its inevitable collision 70-80 Ma [2][5][6][7].

The Collision between India and Asia can be broken into two separate collisions:

  • Tethys Ocean Floor and Asia
  • India and Asia
Tethys Ocean Floor and Asia

During the Mesozoic period, the Atlantic Ocean began to open creating a ripple effect of continents converging on one another [6][8], and the eventual gradual closure of the Tethys Ocean. As India began travelling towards Asia creating a large northward force on the Tethyan oceanic plate. All motion between the converging lithosphere was accommodated by a trench system along the Asian margin[8]. The large amount force generated and the limited ability of the trench system to accommodate the energy resulted in the northward subduction of the Tethys ocean floor beneath the Asian Continent [6][8]. The Tethyan oceanic lithosphere nearly disappeared due to the large scale subduction[8]. The remaining oceanic lithosphere mainly consists of thick sediments deposited along the oceanic-continental plate margin. This sedimentary material was deposited on the Asian continent as the oceanic plate scraped the continental plate as it was subducting. Thick sediments that scrapped off accumulated on the margin and contributed to the later formation of the Himalayan mountain belt [2][6][8].

figure 2.1.2 Example of a recumbent fold located at at Godrevy in Cornwall in England. The rocks are of Devonian age and they were folded during the Variscan orogeny.
India-Asia

As the opening on the Atlantic Ocean continued, India traveled towards Asia at a rate of approximately 6-19 cm/year, slowing to about 4-6 cm/year as the plates neared collision[6]. The continental collision occurred between 70 and 80 Ma years ago. Due to the high density of both plates, upon contact neither plate could be subducted, creating continental crust thickening[2][5][6] around 56-33.9 Ma[5]. Excess sediments became available for crustal thickening through crustal shortening. The north-south crust of Asia was compressed by folding and faulting rock, increasing the thickness to 70 km, double normal depth[2][5][6].

Folds, and faults are forms of rock deformation caused by compressional forces; these forces are strong enough to move ocean sediments thousands of meters above sea level. Folds occur when excess prolonged force causes a rock to fracture or wrinkle [9]. Recumbent folds seen in the Tibetan Plateau[6][9], are present where forces were stronger in one direction and are characterized by the centre of the fold moving from being vertical to horizontal position, as seen in figure 2.1.2. A fault is caused by extreme stress or pressure too great for the rocks internal strength leading to a fracture along a plane of weakness, a fault plane[9]. Horst faults, present Tibetan Plateau [6][9], is the occurrence in which two reverse faults cause rock to be pushed up towards the surface[9].

North-south compression allowed the Tibetan Plateau to expand vertically and horizontally[2][5][6][9], and is evident through sedimentary rock patterns, and paleomagnetism[2]. A difference of 10-50 degrees north and 15-20 degrees south of present latitudes indicates a 2000 +/- 800 km northern displacement of rock in the last 80 Ma years[2].

The Formation of the Tibetan Plateau

This section will use the background information used above and provide a more in-depth explanation of how the collision of the plates created such a vast structure, and the geological processes that took place (folding, faulting, solidification of molten lava before it can escape the surface). I will also provide evidence of how they know this occurred and the processes/priciples used to establish the timeline of events.

Growth of the Tibetan Plateau

The collision between India and Asian is the youngest continent-continent incident to occur[5]. Due to its formation in recent history, the Tibetan Plateau continues to grow today at a rate of approximately 1 cm/year [10][11]. The tectonic plates have actively stopped moving, but the past continental margins are still undergoing compressive forces[2][11]. Although the Plateau is rising by about 1 cm/year, its rate of growth is significantly higher. As the region is experiencing growth, it has to overcome the forces of gravity, and the processes of weathering. If it weren’t for the natural forces reducing the mountains growth rate, the Tibetan Plateau could grow at rates up to 6 cm/year[2][10].

Mitochondrial Function

Mitochondria are small, double membraned organelles found in all cells of the human body. These small units are sometimes referred to as the ‘powerhouse’ of the cells, as they house the structures for ATP production. ATP is the energy currency of life; ATP is created, stored, and used by the body to sustain life [12]. ATP can be produced both in the absence of oxygen (anaerobically) and in the presence of oxygen (aerobically).

Anaerobic Respiration Under Normal Conditions

The electron transport chain is non-functional in the absence of oxygen, as there is no final electron acceptor. Without oxygen a reduced number of ATP molecules is created. The interruption of the electron transport chain creates a reduction is prior reaction activity. Therefore, anaerobic respiration makes use of pyruvate, the final product of glycolysis [13].

Glycolysis is the first step of anerobic respiration and is vital as it produces products that will be used in later stages and produces ATP. Glycolysis takes place in the mitochondrial cytosol and is the splitting of a glucose molecule into two pyruvate molecules and creates 4 ATP as a by-product[14]. Glycolysis consists of 10 Steps, the essential reactions are discussed below:

  • Reaction 1: Glucose enters via the blood stream or glycogenolysis, where is first phosphorylated (biochemical process of adding a phosphate to an organic molecule[15]) by hexokinase, creating glucose 6-phosphate, increasing its reactivity[14]. This reaction requires activation energy of 1 ATP to occur.
  • Reaction 2: Glucose 6-phosphate becomes fructose 6-phosphate
  • Reaction 3: Fructose 6-phosphate is phosphorylated by phosphofructokinase to become fructose 1, 6-diphosphate. This step requires the activation energy of 1 ATP to occur. This reaction creates an unstable molecule that will freely split into 2, 3-carbon molecules[14].
  • Reaction 7: 4 ATP molecules are produced by transferring a phosphate group from a glycolysis substrate to an ADP molecule. This reaction requires enzymatic activity and is referred to as substrate phosphorylation[14].
  • Reaction 10: Pyruvate is the final product of glycolysis via pyruvate kinase. This reaction requires NAD+ and produces NADH. However, glycolysis cannot continue without NAD+ so NADH is recycled back into NAD+ by the aerobic respiration[14].

Aerobic Respiration Under Normal Conditions

This section will cover aerobic ATP synthesis under normal conditions. Explaining the processes, requirement, by-products, products, and limiting factors on the reactions

The Tricarboxylic Acid Cycle
Figure 3.2.1. diagram explaining the tricarboxylic acid cycle *note: this figure does not display the production of FADH2

In order for the electron transport chain to be functional, electrons must be available to pass down. The electrons required for aerobic respiration are supplied by electro-carriers like NADH and FADH2 [16]. These electro-carriers are produced in the Tricarboxylic Acid Cycle, also known as the Kreb’s cycle. This cycle takes 8 steps to complete:

  • Reaction 1: Acetyl CoA bonds with oxaloacetate to form citrate [16]
  • Reaction 2: Citrate is then converted into the isomer isocitrate [16]
  • Reaction 3: Carbon Dioxide is released through the oxidization of isocitrate via isocitrate dehydrogenase to alpha ketoglutarate. This step produces 1 molecule of NADH [16]
  • Reaction 4: Alpha ketoglutarate is oxidized to succinyl CoA. This step produces 1 molecule of NADH[16]
  • Reaction 5: Succinyl CoA is converted to succinate. This step produces 1 molecule of guanosine triphosphate[16]
  • Reaction 6: Succinate is formed into fumarate. This step produces 1 molecule of FADH2 [16]
  • Reaction 7: Fumarate is turned to malate[16]
  • Reaction 8: Malate is formed to oxaloacetate and the cycle can begin once again. This step produces 1 molecule of NADH [16]
The Electron Transport Chain
Figure 3.2.2. diagram explaining the electron transport chain

The Electron transport chain produces the 90%[17] of the ATP within the mitochondria and consists of five protein complexes (I, II, III, IV, and V) within the inner membrane of the mitochondria. NADH and FADH2 act as electron donors by releasing their electrons to complex I and II which are then passed onto the next complex in the chain[18]. This transfer of electrons generates energy which is utilized to move hydrogen ions into the intermembrane space creating an electrical and chemical gradient between the intermembrane space and the membrane. Complex V utilizes the energy created by hydrogen to transform ADP to ATP, via the addition of an inorganic phosphate molecule[18]. As the Hydrogen ions travel back into the matrix, they meet the oxygen, the final electron acceptor in the electron transport chain. Complex IV combines the hydrogen ions with oxygen molecules to form water. Also oxygen is the final electron recipient in the electron transport chain, it is the largest limiting factor for the reaction, without oxygen the process cannot take place [17].

Does Altitude Affect ATP Synthesis Within Mitochondria?

Figure 3.3. diagram explaining the movements of both inhalation and exhalation

Extreme altitudes can limit or prevent some vital processes of the body. As altitude increases, barometric pressure and partial pressure of oxygen decreases[1]. At sea level, the partial pressure of oxygen is roughly 150 mmHg but within the Tibetan Plateau that value can fall as low as 53 mmHg[19]. This decrease in atmospheric oxygen partial pressure, decreases the body’s ability to inspire and utilize oxygen therefore reducing the amount of oxygen dissolved in the blood and compromising oxygen delivery to cellular tissue [1][19][20].

Inhalation and exhalation are achieved through a pressure gradient. Gasses travel from areas of high pressure to low pressure. During inhalation the muscle of the thoracic cavity contract bringing the rib cage up and out, increasing the volume, therefore decreasing the pressure. The decrease in pressure changes the pressure gradient bringing air into the lungs. During exhalation the muscles of the thoracic cavity relax bringing the rib cage down and in, decreasing the volume, therefore increasing the pressure. The increase in pressure changes the pressure gradient pushing air put of the lungs[20][21].

Due to the low barometric and oxygen partial pressure present at extreme altitudes such as in the Tibetan Plateau, the pressure gradient is in not fully functional. The partial pressure of oxygen in the lungs is approximately 104 mmHg[22]. Due to the fact that in places of the Tibetan plateau the partial pressure of oxygen is higher in the lungs than in the atmosphere, inhalation of oxygen is problematic [1][19][20].

A decrease in air inhalation compromises the delivery capability of the vascular system. Arterial oxygen content decreases restricting the diffusion of oxygen between capillaries and mitochondria[1]. A reduction in oxygen content within mitochondrial structures limits the capacity of the organelle to produce ATP. Approximately 90% of the ATP production is from the electron transport chain which in non-functional in conditions of no or low oxygen [1][23][24]. In environments of extreme high altitudes mitochondrial function is severely reduced due to a lack of oxygen availability[1][19][20][23][24].

Physiological Adaptations to Long-Term Exposure

In order to cope with the harsh atmospheric environment of extreme altitudes, the human body is able to acclimatize. On average acclimatization takes between 11-28 days depending on the individual[24], and is done through a number of physiological adaptations:

  • Increase in red blood cell mass helps restore arterial oxygen content but does not fully replenish the oxygen deficit due to lack of dissolved oxygen[1].
  • Down regulation of electron transport chains conserves energy[1].
  • Overall mitochondrial density decreases between 20 and 25% under the 'use it or lose it' principle [1][23][24].
  • Enhanced biomechanics coupling within the mitochondria increases efficiency [1][23][24].
  • Changes in mitochondrial enzyme activities increases efficiency [1][23][24].
  • Within the electron transport chain proton 'leaks' across the inner membrane are controlled[23]
  • Anaerobic respiration becomes more efficient due to the new dependency on the system[23]

Conclusion / Your Evaluation of the Connections

Initially, one may think that human kinetics and geology are widely different fields that do not posses any similar characteristics. However, upon closer inspection it can be seen that while the fields focus in extremely different directions, they can provide opportunity for further learning. The amount of research that could not have been completed without the Tibetan Plateau is astronomical. The extreme altitudes have opened new fields of research and provided new insight into the mysteries of the body. The extensive research may not have been possible without the distinctive topography that the plateau offers. The physiological data that has been collected over decades has been made possible by tectonic plate movement tens of millions of years ago. The events that shaped the world to we see it today have given rise to unimaginable academic opportunity in all fields, and thanks to the hard work of dedicated geologists world-wide we can understand the scenery of the present.

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 A.J. Murray, J.A. Horscroft (2016). "Mitochondrial function at extreme high altitude". Journal of Physiology. 594(5): 1137–1149.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 P Molnar (1989). "The Geological Evolution of the Tibetan Plateau". American Scientist. 77(4): 350–360.
  3. "What is the Highest Point on Earth as Measured from Earth's Center". National Ocean Service. Retrieved June 10, 2020.
  4. Sheather, Tahria. "IS K2 the Next Everest?".
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 A Yin, T.M Harrison (2000). "Geological Evolution of the Himalayan-Tibetan Orogen". Annual Review of Earth and Planetary Sciences. 28(1): 211–280.
  6. 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 "Continental/Continental: The Himalayas". The Geological Society.
  7. 7.0 7.1 7.2 7.3 "Pangea: Ancient Supercontinent". Britannica.
  8. 8.0 8.1 8.2 8.3 8.4 E. Hafkenscheid, M.J.R Wortel, W. Spakman (2006). "Subduction history of the Tethyan region derived from seismictomography and tectonic reconstructions". Journal of Geophysical Research. 111: 1–26.CS1 maint: multiple names: authors list (link)
  9. 9.0 9.1 9.2 9.3 9.4 9.5 "(l). Crustal Deformation Processes: Folding and Faulting". PhysicalGeography.net.
  10. 10.0 10.1 "The Himalayas: Two continents collide". U.S. Geological Survey.
  11. 11.0 11.1 "Tectonic Motion: Making the Himalayas". PBS.
  12. "What are mitochondria?". mitocanada.
  13. "Anaerobic Respiration". Teach Me Physiology.
  14. 14.0 14.1 14.2 14.3 14.4 "Glycolysis". Teach Me Physiology.
  15. "Medical Definition of Phosphorylation". MedicineNet.
  16. 16.0 16.1 16.2 16.3 16.4 16.5 16.6 16.7 16.8 "The TCA Cycle". Teach Me Physiology.
  17. 17.0 17.1 "Electron Transport Chain". Lumen: Biology for Majors.
  18. 18.0 18.1 "Electron Transport Chain". Teach Me Physiology.
  19. 19.0 19.1 19.2 19.3 A.J. Peacock (1998). "Oxygen at high altitude". BMJ: 1063–1066.
  20. 20.0 20.1 20.2 20.3 R.B. Schoene (2001). "Limits of human lung function at high altitude". The Journal of Experimental Biology. 204: 3121–3127.
  21. "How the Lungs Work". National, Heart, Lung, and Blood Institute.
  22. S. Sharma, M.F. Hashmi, D. Rawat (2019). "Partial Pressure Of Oxygen". StatPearls.CS1 maint: multiple names: authors list (link)
  23. 23.0 23.1 23.2 23.3 23.4 23.5 23.6 R.A. Jacobs, R. Boushel, R. Wright-Paradis, C. Calbet, J.A.L. Robach, P. Gnaiger, E. Lundby (2013). "Mitochondrial function in human skeletal muscle following high‐altitude exposure". Experimental Physiology. 98(1): 245–255.CS1 maint: multiple names: authors list (link)
  24. 24.0 24.1 24.2 24.3 24.4 24.5 R.A. Jacobs, C. Siebenmann, M. Hug, M. Toigo, A. Meinild, C. Lundby (2012). "Twenty‐eight days at 3454‐m altitude diminishes respiratory capacity but enhances efficiency in human skeletal muscle mitochondria". The FASEB Journal. 26(12): 5192–5200.CS1 maint: multiple names: authors list (link)
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