Mighty Mitochondria… and Cardiolipin, Too

Mitochondria Are…

Suppose you were asked to name the most important part of your car?  Of course, without an engine you’re not going anywhere.  Without a transmission you’re not going anywhere, either.  So, which is it, the engine or the transmission?  Then, once you get moving, it’s nice to be able to stop.  Brakes, right?  Or perhaps you choose to steer around an obstacle.  Maybe there isn’t a most important part.  Ditto the cell, the unit of structure and function of living things, the smallest unit that can perform an essential life process.  Like your car, the cell has parts.  Considering that you have more than fifty trillion cells, the parts have to be tiny, really tiny.

Each cell is enclosed by a membrane that is made from proteins and a double layer of lipids.  The membrane is vital to the existence and function of the cell because it controls the flow of materials into and out of it, and it keeps the cell’s contents from spilling all over the place.  Not only does the cell have a membrane, but also do its components.  If we were to open and stretch out all the membranes of your body, they’d cover more than forty square miles.  But that’s nothing.  If we uncoiled all your strands of DNA and laid them end to end, they’d reach the sun and back more than once.  When the Psalmist said he was fearfully and wonderfully made, he didn’t realize how right he was.

A component of the cell that shares its architecture is the mitochondrion, sometimes referred to as the power plant of the cell because it makes most of the cell’s supply of adenosine triphosphate (ATP), used as a source of chemical energy.  Like the cell itself, the mitochondrion has an inner and an outer leaf to the membrane.  Mitochondria have other tasks besides making energy, including signaling, cell death, and control of the cell cycle. You already know that different cells have different jobs, each determined by what the nucleus says. Some cells do more work than others and require more energy.  Therefore, some have more mitochondria than others.  You would expect to find more mitochondria in a bicep than in the muscle that blinks an eye.  Each mitochondrion has an intermembrane space—found between the outer and inner membrane leaflets—that controls the movement of proteins. Small molecules have no problem crossing the outer membrane, but larger proteins need to be escorted by a specialized signaling sequence. (sorry about the alliteration)  A noted protein that is localized to the intermembrane area is called cytochrome c, the most abundant and stable cytochrome, principally involved in energy transfer.  Mitochondrial proteins vary depending on the tissue.  More than six hundred types have been identified in the human cardiac mitochondria, for example.  And, even though most of a cell’s DNA is in the nucleus, mitochondria have their own supply.

If there were no mitochondria, the higher animals could not exist.  Mitochondria perform aerobic respiration, requiring oxygen, which is the reason we breathe.  Without them we would have to rely on anaerobic respiration, without oxygen.  That process is too inefficient to support us.  Besides, the lack of mitochondria would reduce energy production by fifteen times, which is far too low to allow survival. A mitochondrion’s DNA reproduces independently of the cell in which it is found.  In humans, this DNA covers more than sixteen thousand base pairs, not very many compared to the whole organism.  Mitochondrial DNA holds thirty-seven genes, all of which are needed for normal function.  Thirteen of these supply information for making enzymes involved in oxidative phosphorylation, which is how ATP is made by using oxygen and simple sugars.  The other twenty-four genes help to make transfer RNA (tRNA) and ribosomal RNA (rRNA), which are chemically related to DNA.  These kinds of RNA are responsible for assembling amino acids into functioning proteins.

Mitochondria are passed on through maternal lineage.  Just as a car’s energy supply from gasoline is in the rear, so is a sperm’s mitochondrial energy—in the tail, which falls off after the sperm attaches to the egg.  This means that any problems, like mitochondrial diseases, necessarily come from the female.  Mitochondrial DNA (mtDNA) does not get shifted from generation to generation, while nuclear DNA does.  It is mtDNA that sends some diseases down the line.  mtDNA, though, is also subject to non-inherited mutations that cause diseases.  Fortunately, these are not passed on, but are accountable for various cancers, such as breast, colon, stomach and liver, diseases that have been attributed to reactive oxygen species.  mtDNA has limited capability to repair itself, so the inherited changes may cause problems with the body’s systems, where the mitochondria are unable to provide sufficient energy for cells to do their work.  The inherited consequences may present as muscle wasting, movement problems, diabetes, dementia, hearing loss, or a host of other maladies.

Some mitochondrial functions are performed only in specific cells.  In the liver, for example, they are able to detoxify ammonia, a job that need not be accomplished anywhere else in the body.  Other metabolic tasks of mitochondria include regulation of membrane potential, apoptosis, calcium signaling, steroid synthesis, and control of cellular metabolism.  You can see that mitochondria are vital to life, and their malfunction can change the rules.  In some mitochondrial dysfunctions there is an interaction of environmental and hereditary factors that causes disease.  Such may be the case with pesticides and the onset of Parkinson’s disease---cellular damage related to oxidative stress.  In other dysfunctions, there may be mutations of certain enzymes, such as coenzyme Q10 deficiency, or aberrations in the cardiolipin molecules that are found inside mitochondria, causative of Barth syndrome, which is often associated with cardiomyopathy.  Mitochondria-mediated oxidative stress may also play a role in Type 2 diabetes.  In cases where misconstrued fatty acid uptake by heart cells occurs, there is increased fatty acid oxidation, which upsets the electron transport chain, resulting in increased reactive oxygen species.  This deranges the mitochondria and elevates their oxygen consumption, resulting in augmentation of fatty acid oxidation.  Merely because oxygen consumption increases does not necessarily mean that more ATP will be manufactured, mostly because the mitochondria are uncoupled.  Less ATP ultimately causes energy deficit, accompanied by reduced cardiac efficiency.

Mitochondria can become involved in a vicious cycle of oxidative stress leading to mitochondrial DNA mutations, which leads to enzyme irregularities and more oxidative stress.  This may be a major factor in the aging process.

Rescue My Mitochondria, Please

The neurodegeneration of Parkinson’s disease is characterized by a loss of dopaminergic neurons and a deficit in mitochondrial respiration.  Exposure to some neurotoxins can present with both characteristics.  In a Parkinson’s model provoked by a drug that was produced to mimic the effects of morphine or meperidine (Demerol), but which interferes with oxidative phosphorylation in mitochondria instead, causing depletion of ATP and cell death, scientists at Columbia University’s Center for Neurobiology and Behavior found that the administration of ketone bodies akin to those used in the treatment of epilepsy were able to attenuate the dopaminergic neurodegeneration and motor deficits induced by the drug (Tieu, 2003).  From this and other studies it has been determined that ketones may play a therapeutic role in several forms of neurodegeneration related to mitochondrial dysfunction (Kashiwaya, 2000).

Moving across the mitochondrial membrane, phosphatidylcholine (PC) limits the phospholipid turnover in both the inner and outer leaflets that epitomizes the membrane defect identified in neurological diseases (Dolis, 1996), including Alzheimer’s, a disease in which impairment of mitochondrial function is part of the pathophysiology.  Substances that inhibit mitochondrial function also activate an enzyme called phospholipase A2 (PLA2) that degrades PC in the membrane (Farber, 2000), but reparation to mitochondria may be realized by administering PC liposomes, as evidenced by Russian studies performed in the early 1990s (Dobrynina, 1991).

Cardiolipin is an important component of the inner mitochondrial membrane, where it makes up about 20% of the lipid composition.  Its operational character is critical to the optimal function of numerous enzymes essential to mitochondrial energy metabolism.  Mitochondrial cardiolipin is distinguished from other phospholipids by the presence of linoleic acid derivatives (Schlame, 1990).  The formation of cardiolipin is dependent upon molecules donated by PC, but because it contains 18-carbon fatty alkyl chains with two unsaturated bonds, it bespeaks a linoleic acid heritage.   The need for linoleic acid, an omega-6 fat, was announced by the American Heart Association several years ago (Harris, 2009).

In the aforementioned Barth syndrome there exist cardiolipin abnormalities and resultant defects in the electron transport chain proteins and the architecture of the mitochondrion.   The electron transport chain (ETC) moves electrons from one cytochrome to another during the production of ATP, terminating at oxygen through a series of increasingly strong oxidative activities.  Those few electrons that fail to make it through the entire process leak and form superoxide, a substantially reactive molecule that contributes greatly to oxidative stress and aging.

Since the heart is rich in cardiolipin, it is more than appropriate to maintain its stores.  And linoleic acid is just the thing to do that.  Dutch researchers found that linoleic acid, readily available from sunflower, hemp, grape seed and other oils, restores and even increases cardiolipin levels (Valianpour, 2003).   Chronic over-consumption of omega-3 fats, such as those from fish oils, creates a deficit of omega-6 fats that interferes with the rate of oxygen use by mitochondria, with consequent decrease of cardiolipin (Yamaoka, 1999) (Hauff, 2006).

Coronary heart disease is a major health issue that may be addressed by supporting cardiolipin integrity, but other conditions likewise respond to such support.  Besides maintaining membrane potential and architecture, cardiolipin provides sustainment to several proteins involved in mitochondrial energy production.  If cardiolipin activity is interrupted or deranged, either through oxidative stress or alterations in acyl chain composition, we may anticipate contending with other pathological conditions, such as ischemia and hypothyroidism, and accelerated aging (Chicco, 2007).  These concerns can be allayed by attending to the status of the tafazzin protein that partly underlies cardiolipin metabolism (Xu, 2006).  Superheroes have long been associated with a sidekick, occasionally with role reversal for the nonce.  Working with linoleic acid to bolster cardiolipin is phosphatidylcholine (PC), which assists protein reconstitution by its ability to transfer acyl groups (Xu, 2003) (Schlame, 1991) and enhance protein signaling.  PC exists in every cell of the body, occupying the outer leaflet of the membrane.  Throughout the course of life, PC levels become depleted and may drop as low as 10% of the membrane in elderly people.  Being so, supplementation is warranted, not only to maintain cardiolipin levels and mitochondrial stability body-wide, but also to retard senescence and to improve brain function and memory capacity.

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