A Deeper Look At Mitochondria

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mitochondria

Adenosine triphosphate (ATP) is The fundamental unit of intracellular energy transfer.  It is produced in mitochondria in humans.  ATP is essential to maintaining the activity and operation of all cells.  The mitochondria create most of the energy they use to generate ATP by creating a proton gradient across the inner mitochondrial membranes.  This energy generation is done largely via the process known as the electron transport chain.  This process is analogous to generating energy to pump water to the high side of a hydroelectric dam, except it’s protons, not water, that are pumped.  This flow of protons back through the metaphorical dam powers the enzyme known as ATP synthase that in turn changes adenosine diphosphate (ADP) into ATP by adding a phosphate group.

The electron transport chain is a system inside of the mitochondria that provides most of the energy that creates the proton gradient that powers the ADP to ATP reaction via ATP synthase.  There are other anaerobic systems for producing ATP in the body, including glycolysis, but they are far less efficient. The electron transport chain is active in producing ATP during aerobic exercise.  At more strenuous levels of exertion, the less efficient glycolysis system generates ATP from pyruvate directly, but this generates lactic acid buildup which leads to fatigue[1].  This aerobic to anaerobic switch under stress also occurs in the brain[2].  As we all know, exercise can increase athletic endurance.  This athletic endurance is tied to mitochondrial capacity and efficiency[3].  There is some evidence that exercise increases mitochondrial capacity in the brain the same way it increases it in the body[4].

Some nootropics interact directly with the mitochondrial membranes.  For example, in a recent study, piracetam protected mitochondria from the bacterial toxin known as lipopolysaccharide by shoring up mitochondrial membranes.  It also improved mitochondrial integrity in healthy cells[5].  In cell models piracetam has been shown to ameliorate degenerative impairment in the mitochondria caused by alzheimers like conditions[6].

Another interesting phenomenon at the mitochondrial membranes are uncoupling proteins.  These proteins induce thermogenesis in mitochondria by letting electrons leak back through the membrane without generating ATP.  It’s similar to opening up a flood gate to let water spill through the dam without going through the generators.  This is another way of releasing stored energy besides aerobic energy generation.  This process happens in  mammals during hibernation.  This process can be upregulated in brown adipose tissue found in the body by inhibiting PDE3 and PDE4[7].  This uncoupling mechanism can induce thermogenic weight loss[8].

There are four different complexes in the electron transport chain that oxidize substrates to generate the energy to transfer protons out of the mitochondrial membrane.  Each step of oxidation creates an incremental amount of energy for ATP production.  The last step of the chain involves a chemical reaction with oxygen.  Sometimes reactants skip a few steps and react directly with oxygen creating damaging free radicals[9].  The three different complexes are NADH to NAD+ (Complex I), Succinate to Fumarate (Complex II) and CoQH2 to CoQ (Complex III) and O2 -> H20 (Complex IV).  These complexes are amenable to optimization in various ways.

Our first metaphorical pumping station, Complex I, turns NADH to NAD+.  It pumps protons by transferring electrons to coenzyme Q10 turning it into ubiquinol which, through a series of reactions, pump protons out of the membrane and to the high side of the metaphorical dam.  Coenzyme Q10 and ubiquinol are both sold as supplements.  Improvements in exercise performance for users of supplemental coenzyme Q10 are not significant[10] nor has it shown much benefit in parkinson’s disease[11].  The reduced form of coenzyme Q10, ubiquinol, has some interesting data.  It enhanced athletic performance in healthy athletes[12] and has shown some beneficial effects in studies in managing diabetes[13].

A synthetic analog of coenzyme Q10 known as idebenone has some interesting effects at complex 1.  Idebenone’s mechanism of action may be in its ability to help utilize NADH to pump protons when complex 1 is not functioning properly[14], possibly via complex III[15]. In studies it increased nerve growth factor production in an animal model of brain damage[16].  In another study it slowed down the development of dementia symptoms in Alzheimer’s patients[17].

Complex ||, which converts succinate to fumarate can be protected from dysfunction by a combination of glutathione and vitamin C[18].  In general studies have shown that vitamin C helps complexes I-IV of the electron transport chain function properly[19].

Complex III, uses cytochrome c to contribute to the mitochondrial power generation by converting ubiquinol back to coenzyme q10.  There is some evidence that luteolin protects this process from antimycin-a which inhibits cytochrome c[20].

Complex IV, uses cytochrome c oxidase to turn oxygen to water for the last step of the electron transport chain. Interestingly, some evidence suggests that laser light therapy can increase its activity[21].  Some studies were also done on methylene blue that provided some evidence for positive effects on cytochrome C oxidase[22] in alzheimer’s patients.

These various complexes are like pistons in a gas powered pump.  With each turn of the crank each cylinder fires and pushes the proton “water” up to the top of the dam.  The mitochondria are at the core of many dysfunctions and problems in human health, including aging. Thus, targeting optimization and protection of these cell components is a fruitful area of investigation for those who want to enhance and improve their mental and physical performance.

Additional posts by Abelard Lindsay (@ciltep):

References:

 

[1] Sahlin K, Katz A, Henriksson J. Redox state and lactate accumulation in human skeletal muscle during dynamic exercise. Biochem J. 1987;245(2):551-6. PMID http://www.ncbi.nlm.nih.gov/pubmed/3663177

[2] Zeiger SL, Stankowski JN, Mclaughlin B. Assessing neuronal bioenergetic status. Methods Mol Biol. 2011;758:215-35. PMID 21815069

[3] Bishop DJ, Granata C, Eynon N. Can we optimise the exercise training prescription to maximise improvements in mitochondria function and content?. Biochim Biophys Acta. 2014;1840(4):1266-75. PMID 24128929

[4] Aguiar AS, Stragier E, Da luz scheffer D, et al. Effects of exercise on mitochondrial function, neuroplasticity and anxio-depressive behavior of mice. Neuroscience. 2014;271:56-63. PMID 24780767

[5] Gupta S, Verma DK, Biswas J, et al. The metabolic enhancer piracetam attenuates mitochondrion-specific endonuclease G translocation and oxidative DNA fragmentation. Free Radic Biol Med. 2014;73C:278-290. PMID 24882422

[6] Stockburger C, Kurz C, Koch KA, Eckert SH, Leuner K, Müller WE. Improvement of mitochondrial function and dynamics by the metabolic enhancer piracetam. Biochem Soc Trans. 2013;41(5):1331-4.  PMID 24059528

[7] Kraynik SM, Miyaoka RS, Beavo JA. PDE3 and PDE4 isozyme-selective inhibitors are both required for synergistic activation of brown adipose tissue. Mol Pharmacol. 2013;83(6):1155-65. PMID 23493317

[8] Boon MR, Bakker LE, Meinders AE, Van marken lichtenbelt W, Rensen PC, Jazet IM. [Brown adipose tissue: the body's own weapon against obesity?]. Ned Tijdschr Geneeskd. 2013;157(20):A5502. PMID 23676126

[9] Mailloux RJ, Jin X, Willmore WG. Redox regulation of mitochondrial function with emphasis on cysteine oxidation reactions. Redox Biol. 2013;2:123-39. PMID 24455476

[10] Bloomer RJ, Canale RE, Mccarthy CG, Farney TM. Impact of oral ubiquinol on blood oxidative stress and exercise performance. Oxid Med Cell Longev. 2012;2012:465020. PMID 22966414

[11] Beal MF, Oakes D, Shoulson I, et al. A randomized clinical trial of high-dosage coenzyme q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol. 2014;71(5):543-52. PMID 24664227

[12] Alf D, Schmidt ME, Siebrecht SC. Ubiquinol supplementation enhances peak power production in trained athletes: a double-blind, placebo controlled study. J Int Soc Sports Nutr. 2013;10:24. PMID 23627788

[13] Mezawa M, Takemoto M, Onishi S, et al. The reduced form of coenzyme Q10 improves glycemic control in patients with type 2 diabetes: an open label pilot study. Biofactors. 2012;38(6):416-21. PMID 22887051

[14] Haefeli RH, Erb M, Gemperli AC, et al. NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels. PLoS ONE. 2011;6(3):e17963. PMID 21483849

[15] Giorgio V, Petronilli V, Ghelli A, et al. The effects of idebenone on mitochondrial bioenergetics. Biochim Biophys Acta. 2012;1817(2):363-9. PMID 22086148

[16] Nitta A, Murakami Y, Furukawa Y, et al. Oral administration of idebenone induces nerve growth factor in the brain and improves learning and memory in basal forebrain-lesioned rats. Naunyn Schmiedebergs Arch Pharmacol. 1994;349(4):401-7.PMID 8058112

[17] Bergamasco B, Scarzella L, La commare P. Idebenone, a new drug in the treatment of cognitive impairment in patients with dementia of the Alzheimer type. Funct Neurol. 1994;9(3):161-8. PMID 7988944

[18] Ehrhart J, Zeevalk GD. Cooperative interaction between ascorbate and glutathione during mitochondrial impairment in mesencephalic cultures. J Neurochem. 2003;86(6):1487-97. PMID 12950457

[19] Ghneim HK, Al-sheikh YA. The effect of aging and increasing ascorbate concentrations on respiratory chain activity in cultured human fibroblasts. Cell Biochem Funct. 2010;28(4):283-92. PMID 20517892

[20] Choi EM. Luteolin protects osteoblastic MC3T3-E1 cells from antimycin A-induced cytotoxicity through the improved mitochondrial function and activation of PI3K/Akt/CREB. Toxicol In Vitro. 2011;25(8):1671-9. PMID 21782929

[21] Albuquerque-pontes GM, Vieira RD, Tomazoni SS, et al. Effect of pre-irradiation with different doses, wavelengths, and application intervals of low-level laser therapy on cytochrome c oxidase activity in intact skeletal muscle of rats. Lasers Med Sci. 2014; PMID 24957189

[22] Atamna H, Kumar R. Protective role of methylene blue in Alzheimer’s disease via mitochondria and cytochrome c oxidase. J Alzheimers Dis. 2010;20 Suppl 2:S439-52. PMID 20463399

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About the Author

Abelard Lindsay

I am the creator of the CILTEP stack. View the thread on Longecity | @ciltep