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What You Need to Know About Mitchondrial Dysfunction and the Heart

The Mitochondrial Theory of Aging

The mitochondrial theory of aging (MTA) and the free-radical theory of aging (FRTA) are closely related, and were in fact proposed by the same researcher about 20 years apart. Both theories suggest that free-radicals damage DNA over time, causing one to age, while the MTA just adds the mitochondria and its production of free radicals into the equation. These theories and the understanding we now have of free radicals are the reason that antioxidants are such popular supplements and topics of discussion today.

The Paradox

Mitochondria are like little cells within our cells (see Figure 1 ). They are the energy producing organelles of the body. The more energy a certain tissue requires such as the brain and the heart, the more mitochondria those cells contain. What makes mitochondria interesting is that they have their own set of DNA. What makes them paradoxical is that the more energy they produce, the more DNA-damaging free radicals they produce! Mitochondrial DNA damage appears to be caused by the natural by-products of energy or ATP production, meaning that the very process that is meant to sustain life is what eventually causes the dysfunction and death of the cell! Mitochondria may well hold the key to function and dysfunction, and ultimately to life and death!Think of it this way: all cells, tissues and thus body parts require ATP, or energy, to function properly. If DNA holds the blueprint for the proper function of a cell, then any change in the blueprint will change how the cell functions. If the mitochondria do not function properly, then they cannot fulfill their role in producing energy, meaning that the cell will lose its ability to function adequately.

Many Mechanisms

Dysfunctions of the mitochondria have been proposed in the development of a whole host of degenerative diseases, including diabetes, high blood pressure, Alzheimer’s disease, neurodegeneration and cancer.4 Researchers have mostly focused on those related to the heart and the brain because they require large amounts of oxygen and energy and are so dense in mitochondria, meaning that mitochondrial dysfunction has a huge impact on the functioning of these organs.

What We Currently Know

Diabetes, Endothelial Dysfunction, Blood Pressure & Reduced Nitric Oxide

In diabetes, high blood sugar and high blood lipids that have been oxidized or glycated impair the function of the mitochondrial enzymes which results in an overproduction of free radicals. These free radicals damage the mitochondrial DNA, make the mitochondria dysfunctional and alter various pathways in the endothelial cells that initiate atherosclerosis and cardiomyopathy (heart muscle disease).1They also reduce the activity of Nitric Oxide Synthase in endothelial cells, which reduces nitric oxide production and endothelial-dependent vasodilation, resulting in high blood pressure.2,3 This effect has been shown in the arterioles of subjects with type 2 diabetes versus controls without the disease. In those with diabetes, endothelial function was impaired, mitochondrial density was lower, flow – mediated dilation (a measure of blood vessel responsiveness to blood pressure) was lower, and mitochondrial superoxide (a free radical) production was higher.9

Toxic Fat!

Mitochondria are also involved in lipid metabolism. If the mitochondria are dysfunctional, then lipid metabolism becomes imbalanced. It is suggested that this dysfunctional partnership may complicate type 1 diabetes through mitochondrial dysfunction in the pancreatic beta cells that produce insulin, disrupting the metabolism of fats and sugars. In type 2 diabetes, it is thought that mitochondrial dysfunction also occurs in fat cells, inhibiting the proper metabolism of fats. This allows excess fats to circulate and be taken up by other cells such as those pancreatic beta cells, resulting in lipotoxicity (fat toxicity) and perpetuating the mitochondrial dysfunction.5 In humans, a high-fat diet has been shown to increase mitochondrial production of free radicals in muscles, and that when free radical production was limited with a targeted drug, insulin sensitivity was preserved!6

Calcium Regulation

Dysfunctional mitochondria are also a hallmark of heart muscle remodeling in disease. It is now thought that mitochondria help regulate calcium flux in the heart cells, helping to regulate its function.7,8 Calcium is required for the contraction of muscles, including the heart. If the mitochondria are dysfunctional, their ability to buffer calcium as well as supply energy to the heart are greatly compromised.

Potential Treatment Options Under Study

Exercise for Endothelial and Mitochondrial Dysfunction

It is known that exercise can actually stimulate the multiplication of mitochondria in muscle tissue. This makes sense because if the muscles require more energy, the body will need to make sure the machinery to make that extra energy is available. We also know that exercise improves endothelial function. One study found that in patients with coronary artery disease (CAD), 33% of them had mitochondrial dysfunction. Those 33% tended to have lower physical activity levels, which was associated with greater endothelial dysfunction. The reverse was also true.10 This shows that lower physical activity levels are associated with greater mitochondrial dysfunction and endothelial dysfunction in CAD patients, that more physical activity could actually reduce both mitochondrial and endothelial dysfunction, and that both types of dysfunction could be related!

Nutritional Support for the Mitochondria

1. Lipoic Acid & Acetyl-L-Carnitine

Calcification of the blood vessels is an important concern today because it leads to hardening of the arteries. Alpha lipoic acid is known to be a mitochondrial antioxidant that preserves or improves mitochondrial function. However, it has now also been shown in vitro and in an animal study that lipoic acid can prevent arterial calcification, and that arterial calcification may even be related to mitochondrial dysfunction!12 Since lipoic acid is so important for mitochondrial health, methods are under study to increase lipoic acid synthase production, the enzyme responsible for making lipoic acid in the body.11 A human study on CAD patients has given further proof of the relationship between endothelial dysfunction, mitochondrial dysfunction and heart disease. CAD patients were given lipoic acid and acetyl-L-carnitine for 8 weeks and then a placebo for 8 weeks. L-Carnitine helps shuttle fatty acids into the mitochondria in order to make energy. The treatment was found to relax the blood vessels in all patients. In patients with higher blood pressure and in those with metabolic syndrome, blood pressure decreased by 9mmHg! 13This shows that treating mitochondrial dysfunction can improve blood vessel function and therefore blood pressure. This is indeed a novel approach!


Figure 1. Many mitochondria are found within a single cell. Mitochondria use fat and sugar substrates to produce energy (ATP) via the citric acid cycle and the electron transport chain. Mitochondria also have their own set of DNA.

2. Co-Enzyme Q10

CoQ10 is perhaps the most popular mitochondrial enzyme and antioxidant. It is already well known that statin drugs taken for high cholesterol severely reduce CoQ10 levels, which ironically Advances 23causes other negative cardiovascular side effects. However, a human study on CAD patients has now shown that over 8 weeks of supplementing with 300mg of CoQ10 reversed mitochondrial dysfunction (as measured by a reduced lactate:pyruvate ratio) and improved endothelial function (as measured by increased flow-mediated dilation)!14

3. Other Mitochondrial Antioxidants

Other natural compounds that have been shown to have antioxidant effects in the mitochondria include resveratrol, found in wine and grapes, curcumin from turmeric and EGCG, found abundantly in green tea extract. However, human studies have not been conducted for these compounds in mitochondrial dysfunction.16,18

A New Name

So recognized is the role of mitochondrial dysfunction in many diseases that a new term has been coined for this phenomenon: bioenergetic dysfunction.15 Bioenergetic dysfunction is now known to be related to a gamut of diseases including diabetes, hypertension, arterial calcification, Alzheimer’s disease, and even autism (see Figure 2).4,16,17 The most recent research is applying current knowledge of bioenergetics dysfunction to cancer treatments including chemotherapies.16

Quality Mitochondria Equals Quality Health

Not only the quantity of mitochondria but the quality of those mitochondria is important for good health. Exercise can increase the number of mitochondria, but the health of those mitochondria must be preserved with targeted mitochondrial antioxidants. Failure to do so can result in mutations to the mitochondrial DNA. The mitochondria need to be functioning adequately enough to destroy damaged or mutated machinery (mitophagy) in order to remain healthy. In fact, this regulated recycling process is essential in order to lengthen one’s lifespan according to the caloric restriction diet (which by the way is the only proven method to lengthen one’s lifespan and healthspan).15 The bottom line is that all evidence is pointing toward the mitochondria as the key holders to health.

References

1. Giacco F & Brownlee M. Oxidative Stress and Diabetic Complications. Circulation Research. 2010; 107: 1058-1070.

2. Shen GX. Oxidative stress and diabetic cardiovascular disorders: roles of mitochondria and NADPH oxidase. Canadian Journal of Physiology and Pharmacology, 2010, 88:241-248.

3. Shen GX. Mitochondrial Dysfunction, Oxidative Stress and Diabetic Cardiovascular Disorders. Cardiovasc Hematol Disord Drug Targets. 2012 Oct 1.

4. Gruber J, Fong S, Chen CB, Yoong S, Pastorin G, Schaffer S, Cheah I, Halliwell B. Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing. Biotechnol Adv. 2012 Sep 27.

5. Vamecq J, Dessein AF, Fontaine M, Briand G, Porchet N, Latruffe N, Andreolotti P, Cherkaoui-Malki M. Mitochondrial dysfunction and lipid homeostasis. Curr Drug Metab. 2012 Sep 4.

6. Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT, Price JW 3rd, Kang L, Rabinovitch PS, Szeto HH, Houmard JA, Cortright RN, Wasserman DH, Neufer PD. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009 Mar;119(3):573-81.

7. Verdejo HE, Del Campo A, Troncoso R, Gutierrez T, Toro B, Quiroga C, Pedrozo Z, Munoz JP, Garcia L, Castro PF, Lavandero S. Mitochondria, myocardial remodeling, and cardiovascular disease. Curr Hypertens Rep. 2012 Dec;14(6):532-9.

8. Sullivan PG, Balke CW & Esser KA. Mitochondrial Buffering of Calcium in the Heart: Potential Mechanism for Linking Cyclic Energetic Cost With Energy Supply? Circulation Research. 2006; 99: 109-110.

9. Kizhakekuttu TJ, Wang J, Dharmashankar K, Ying R, Gutterman DD, Vita JA, Widlansky ME. Adverse alterations in mitochondrial function contribute to type 2 diabetes mellitus-related endothelial dysfunction in humans. Arterioscler Thromb Vasc Biol. 2012 Oct;32(10):2531-9.

10. Luk TH, Dai YL, Siu CW, Yiu KH, Li SW, Fong B, Wong WK, Tam S, Tse HF. Association of lower habitual physical activity level with mitochondrial and endothelial dysfunction in patients with stable coronary artery disease. Circ J. 2012 Oct 25;76(11):2572-8.

11. Padmalayam I. Targeting mitochondrial oxidative stress through lipoic acid synthase: a novel strategy to manage diabetic cardiovascular disease. Cardiovasc Hematol Agents Med Chem. 2012 Sep;10(3):223-33.

12. Kim H, Kim HJ, Lee K, Kim JM, Kim HS, Kim JR, Ha CM, Choi YK, Lee SJ, Kim JY, Harris RA, Jeong D, Lee IK. α-Lipoic acid attenuates vascular calcification via reversal of mitochondrial function and restoration of Gas6/Axl/Akt survival pathway. J Cell Mol Med. 2012 Feb;16(2):273-86.

13. McMackin CJ, Widlansky ME, Hamburg NM, Huang AL, Weller S, Holbrook M, Gokce N, Hagen TM, Keaney JF Jr, Vita JA. Effect of combined treatment with alpha-Lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease. J Clin Hypertens (Greenwich). 2007 Apr;9(4):249-55.

14. Dai YL, Luk TH, Yiu KH, Wang M, Yip PM, Lee SW, Li SW, Tam S, Fong B, Lau CP, Siu CW, Tse HF. Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial. Atherosclerosis. 2011 Jun;216(2):395-401.

15. Hill BG, Benavides GA, Lancaster JR, Ballinger S, Dell’italia L, Zhang J, Darley-Usmar VM. Integration of cellular bioenergetics with mitochondrial quality control and autophagy. Biol Chem. 2012 Jun 23.

16. Kang J, Pervaiz S. Mitochondria: redox metabolism and dysfunction. Biochem Res Int. 2012.

17. Davis RE, Williams M. Mitochondrial function and dysfunction: an update. J Pharmacol Exp Ther. 2012 Sep;342(3):598-607.18. Rimbaud S, Ruiz M, Piquereau J, Mateo P, Fortin D, Veksler V, Garnier A, Ventura-Clapier R. Resveratrol improves survival, hemodynamics and energetics in a rat model of hypertension leading to heart failure. PLoS One. 2011;6(10):e26391

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