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  #1   ^
Old Sat, Jan-06-18, 13:17
teaser's Avatar
teaser teaser is offline
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Plan: mostly milkfat
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Default Heart failure, mitochondria, and diabetes

https://www.sciencedaily.com/releas...80105135241.htm

Quote:
Excess fat disrupts heart cell's energy system
Lipid overload in heart cells alters mitochondrial shape and disrupts the cardiac mitochondrial network

A University of Iowa study has identified how excess fat in the heart, a common feature in diabetes and obesity, can harm the cells' essential ability to produce energy. Researchers believe the mechanism may contribute to the two- to five-fold increased risk of heart failure in people with diabetes.

The heart is the most energy-hungry organ in the body. Just like a combustion engine burning fuel to power the pistons, healthy heart cells consume fuel molecules to create the necessary energy to keep the heart pumping. This essential energy production takes place inside mitochondria, the self-contained "powerplant" organelles inside cells.

Although mitochondria in a healthy heart primarily use fatty acids as fuel, they can easily adapt to use other fuel molecules as needed, including glucose, lactate, and ketone bodies. Diabetes, however, reduces the heart muscle's metabolic adaptability and causes heart cells to overuse fat as a metabolic fuel.

The study, published in Circulation Research, found that this cardiac lipid overload leads to numerous small, misshapen mitochondria that don't produce energy as efficiently as normal mitochondria. Previous research from the UI team has suggested that problems with mitochondrial energy production may play a role in heart failure associated with diabetes.

"Diabetes, which affects almost 30 million Americans, significantly increases the risk of heart failure, and one of the cardinal manifestations of the hearts of people with diabetes is the tendency to overuse fat as a metabolic fuel, which ultimately leads to mitochondrial and cardiac damage," explains study leader E. Dale Abel, MD, PhD, professor and departmental executive officer of internal medicine at the UI Carver College of Medicine and director of the Fraternal Order of Eagles Diabetes Research Center at the UI. "We have demonstrated and detected how increasing the amount of fat (lipid) that the heart consumes leads to dramatic changes in the structure and function of the mitochondria in the heart. These studies provide a new window into how these changes to mitochondria could occur in the lipid-overloaded heart."

The UI team used genetically modified mice that mimic the increased fatty acid uptake (lipid overload) that characterizes diabetes to investigate the consequences of cardiac lipid overload on mitochondria. A novel 3-D electron microscopic cellular imaging technique developed by colleagues in Germany allowed the researchers to directly observe the structural changes to the mitochondria -- rather like putting on a virtual reality headset inside the cardiac muscle cell, says Abel. In the mouse model, lipid uptake to heart is doubled. This modest increase resulted in mitochondria that became thinner and more twisted than mitochondria in healthy heart cells. These structural changes (almost like a noodle snaking through the heart) lead to an appearance of mitochondrial fragmentation when imaged by conventional electron microscopy.

The study also revealed the molecular cause of the change in mitochondrial structure. Prolonged lipid overload leads to increased levels of damaging substances called reactive oxygen species (ROS). The excess ROS disrupts the mitochondrial network by altering the activity of several important proteins that help control the size and shape of mitochondria.

Removing the excess ROS by overexpressing a molecule that helps "mop up" ROS molecules restored normal-looking mitochondria, which worked properly, despite the lipid overload.

Surprisingly, using the same approach to remove ROS in normal heart cells led to mitochondria that were four times as large as normal, suggesting that ROS levels are inversely proportional to mitochondria size.

The findings suggest that cardiac lipid overload disrupts normal mitochondrial structure, which may impair energy production and compromise heart function.


Interesting that the new imaging technique shows mitochondrial fragmentation in the heart, at least, to be an artifact of conventional electron microscopy.

Quote:
causes heart cells to overuse fat as a metabolic fuel.


This part, not so much. Athletes get fattier muscles, paired with an increase in muscle insulin sensitivity. Type II diabetics and people with insulin resistance get fattier muscles, paired with a decrease in muscle insulin sensitivity. Aside from that, there's a big difference from any organ taking in lots of free fatty acids and lots of glucose, and an organ taking in free fatty acids and lower amounts of glucose. If your heart's main fuel is fat, but most of what you eat is glucose, that's a far cry from being on a low carb diet and burning mostly fat.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5284490/

More about mitochondria form and function in diabetes.

Quote:
Mitochondria are highly dynamic organelles and play a very important role in maintaining homeostasis. Furthermore, they are the main source of ROS in the organism and control cellular homeostasis, cell death and apoptosis. Therefore, their functionality is vital for life. Mitochondrial dynamics and mitochondrial biogenesis are processes which are impaired in conditions of insulin resistance in general, and in type 2 diabetes in particular. Therefore, these processes are promising pharmaceutical targets for the treatment of this group of age-related diseases.

The role of mitochondrial dynamics in energy expenditure and nutrient utilization is emerging, and mitochondrial biogenesis, dynamics and mitophagy are related to adaptation to metabolic demands. Nutrient excess induces mitochondrial impairment and fragmentation and can inhibit autophagic flux and promote ROS production. This review has discussed how disturbances in mitochondrial dynamics contribute to the development of insulin resistance condition and type 2 diabetes.



https://newatlas.com/fasting-increa...-harvard/52058/

And a bit on fasting's effects on mitochondria.

Quote:
Mitochondria are a little like tiny power plants inside our cells. Last year a team of researchers led by Newcastle University successfully showed how mitochondria are fundamental to the aging of cells. The new research from Harvard shows how the changing shapes of mitochondrial networks can affect longevity and lifespan, but more importantly the study illustrates how fasting manipulates those mitochondrial networks to keep them in a "youthful" state.

Inside cells mitochondrial networks generally alternate between two states: fused and fragmented. Using nematode worms, an organism useful for studying longevity as it only lives for two weeks, the study found that restricted diets promotes homeostasis in mitochondrial networks allowing for a healthy plasticity between these fused and fragmented states.

"Our work shows how crucial the plasticity of mitochondria networks is for the benefits of fasting. If we lock mitochondria in one state, we completely block the effects of fasting or dietary restriction on longevity," says Mair.
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  #2   ^
Old Sat, Jan-06-18, 13:56
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nawchem nawchem is offline
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Teaser it's a little bit over my head. When they say excess fat, do they mean body fat or dietary fat?

People with hypothyroidism are more prone to dying of heart disease also. Would it be because we can't burn free fatty acids when the thyroid levels are low.

I've also read that once thyroid levels are restored there's a period of time before the mitochondria normalize. Is this article saying that can be facilitated by fasting?
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  #3   ^
Old Sat, Jan-06-18, 14:27
teaser's Avatar
teaser teaser is offline
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Posts: 12,692
 
Plan: mostly milkfat
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Whatever they actually meant, I think they should have meant body fat, with what constitutes "excess" varying from person to person. Past a certain level of storage in fat tissue itself, excess fat starts to accumulate in all sorts of lean tissue, muscle, liver, heart, pancreas. With the exception of some increase fat in muscle in athletes, it's generally a bad deal and interferes with mitochondrial function etc.

Quote:
People with hypothyroidism are more prone to dying of heart disease also. Would it be because we can't burn free fatty acids when the thyroid levels are low.


I have seen suggestions that for people with heart failure, reduced energy due to hypothyroidism could make things worse. You could see a vicious cycle, heart failure reduces oxygenation of blood, higher fat vs. carbohydrate increases reliance on oxygen for energy supply. A ketogenic diet is different vs. a diet that's just high in both fat and carbohydrate, Dominic D'Agostino's work on the ketogenic diet started with the observation that people and animals were more resilient in low oxygen conditions when ketones were elevated.

Hypothyroid also seems to increase risk of atherosclerosis, and there seems to be some effect on vasodilation. I've only skimmed through this, but it's interesting;

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318631/

"Thyroid and the Heart."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590606/

Quote:
Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling


I haven't really looked into thryoid's effects on mitochondria. There's just so much of this stuff. This looks relevant, I haven't read it, just sticking this here to read later and in case anybody else is interested.
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  #4   ^
Old Sat, Jan-06-18, 15:58
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nawchem nawchem is offline
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Thanks teaser great papers. I skimmed and found this interesting tidbit in the mito one.

Taken together, our data demonstrate that T3 maintains increased hepatic metabolic activity by promoting turnover of the intracellular pool of mitochondria through increased rates of mitophagy and mitochondrial synthesis. Thus, induction of mitophagy by intracellular ROS derived from increased mitochondrial energy production can help prevent the accumulation of damaged mitochondria as well as promote cellular health and function in hypermetabolic states. Mitochondrial function and its quality control are important factors in metabolic diseases such as diabetes and nonalcoholic fatty liver disease as well as aging.51,52 Our studies thus suggest that T3 or its analogs may be beneficial for treating these conditions by promoting mitochondrial turnover.53 Lastly, our finding that T3 stimulation of mitophagy occurs via a pathway involving increased ROS production; intracellular Ca2+ increase; CAMKK2, PRKAA1/AMPK, and ULK1 activation now provides several new therapeutic targets for maintaining mitochondrial number and function that could lead to novel treatments for metabolic and aging-related diseases.54
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