The Dark Side of the Force   |  71

For example, when this happens to the cardiovascular system, we

call it coronary artery disease (CAD), angina, or congestive heart
failure (CHF).
Following this train of thought, I’ll start my discussion on health
conditions with cardiovascular disorders.

The Role of Mitochondria

in Cardiovascular Disease
Cardiovascular disease is a broad category of health conditions and is
likely of great interest to the majority reading this book because it’s a
leading cause of death globally (often alternating with cancer for the
top two spots, depending on the country you’re looking at). Conditions
such as angina, hypertension, congestive heart failure, ischemia, and
diastolic dysfunction all have their roots in mitochondrial energy.
Not only can these conditions arise from a cellular energy deficiency,
but they can also leak the purine building blocks of ATP out of the
cell. Interestingly, when purine building blocks leak from the cell,
they are metabolized to uric acid, and high uric acid in patients is
often reflective of dysfunctional ATP metabolism (an important point
to understand for clinicians treating gout, for example).
It can take up to two weeks (and in some cases months) for the
heart to produce enough ATP, by natural, built-in mechanisms, to
offset the deficit caused by ischemia. Also, since the heart is constantly
consuming ATP, it’s difficult to make up for this energy deficit quickly,
and most patients with ischemia will need to take targeted nutritional
therapy to help restore the energy balance. I’ll discuss these nutri-
tional therapies in depth in chapter 3.

Understanding Smooth Muscles

A large part of our cardiovascular system involves smooth muscles
(muscles not under voluntary control), so let’s review their signifi-
cance and what their normal and abnormal functioning look like.
Smooth muscles are found in the blood vessels of the cardiovascular
system, but are also contained within other organs and tubes in the
body, including the stomach, intestines, bladder, airways, uterus, and
72  |  Mitochondria and the Future of Medicine

the penile and clitoral cavernosal sinuses. Bundles of smooth muscle

cells are also attached to the hairs of the skin and to the iris and lens
of the eye.
Smooth muscle cells receive input from the autonomic nervous
system (which is the part of the nervous system not under voluntary
control, e.g., the part that digests food). In addition to the autonomic
nervous system, smooth muscles are controlled by hormones and
other local chemical signals. Smooth muscle cells also develop tonic
and phasic contractions in response to changes in load or length. By
contrast, skeletal muscles are under voluntary control, and these are
the muscles we consciously contract and relax when we decide to
move our arms or go for a walk.
Contraction (shortening of muscle cells) in smooth muscles is a
highly regulated process. In some smooth muscle cells, the contrac-
tion is maintained at a low level in the absence of external stimuli.
This activity results in what is known as smooth muscle tone and its
intensity can be varied. Keep this in mind when I discuss how this
relates to conditions such as hypertension (see “Coenzyme Q10” on
page 144).
Regardless of the stimulus, a smooth muscle contraction is initi-
ated by calcium ions entering the cytosol (from the sarcoplasmic
reticulum—a membrane-bound structure in muscle cells that stores
calcium) and binding to a calcium-binding messenger protein called
calmodulin. This stimulates another protein called myosin (the protein
that contracts and is dependent on ATP) to attach to actin in cross-
bridge cycling.
Initiation of relaxation, on the other hand, begins with the removal
of calcium ions from the cytosol and stimulation of an enzyme that
deactivates myosin (referred to as myosin phosphatase).

The Importance of Smooth Muscle Relaxation

Many people don’t realize that muscle relaxation (elongation of a
muscle cell) requires considerable amounts of energy. Whether it is a
conscious decision to relax skeletal muscles or the involuntary relax-
ation of smooth muscles, the process requires a decreased concentra-
tion of calcium ions. All this calcium must move out of the cytosol
 The Dark Side of the Force   |  73

and into the sarcoplasmic reticulum. However, this process requires

the use of a pump because the calcium must move up the concen-
tration gradient—and going against the gradient requires energy.
That energy, of course, comes from ATP. The enzyme embedded in
the membrane of the sarcoplasmic reticulum, called calcium-magne-
sium-ATPase (Ca-Mg-ATPase), when activated, binds two calcium
ions, which are then transferred to the inner part of the sarcoplasmic
reticulum and released (sequestered, ready for the next stimulus
signaling a contraction).
This pump also has two ATP-binding sites, and both sites must have
ATP attached for it to work. However, there are intricacies. The first
ATP-binding site has a high affinity for ATP, and therefore, any ATP
in the vicinity binds to this site readily. Once bound to this site,
ATP releases its energy, and is turned into ADP. The second
ATP-binding site does not attract ATP so easily. In fact, the only way
for ATP to bind to the second site is to ensure a high concentra-
tion of ATP so that hopefully one will just “fall” into the binding
site. Building up this concentration obviously requires significant
amounts of ATP to be produced.
The state of rigor mortis, when our muscles become tense and rigid
after death, is a good example of how relaxation requires more ATP
than contraction. In death, fuel and oxygen are no longer delivered
to the muscles, and ATP production stops. Without enough ATP, the
calcium ions cannot be pumped out of the cell, and the muscles can
no longer “relax.”
Magnesium ions are also necessary for the activity of the Ca-Mg-
ATPase; they bind to the catalytic site of this enzyme to mediate the
reaction. Without magnesium, this enzyme cannot function and
relaxation of the smooth muscle cannot occur (which can lead to
things like high blood pressure, heart problems, or restricted breath-
ing). For those who might have heard magnesium is great for muscle
function and relaxation but didn’t know how or why, now you know.

The Basics of Cardiac Physiology

Now let’s discuss the other part of the cardiovascular system: the heart
itself. The human heart has four chambers—two upper chambers
74  |  Mitochondria and the Future of Medicine

(called the left and right atria) and two lower chambers (called the left
and right ventricles). In terms of heart function, systole describes the
stage of a heartbeat when the ventricles contract, squeezing the blood
out to the arteries. This contraction ejects most of the blood out of the
ventricles, and the percent of blood that’s pumped out (relative to its
starting point when “relaxed”) is called the ejection fraction (normal
range is 50–70 percent). While it’s easy to see how contraction of the
heart requires energy, this stage requires the least amount of energy in
the cycle of a heartbeat. Muscle cells in general (not just smooth muscle
cells), including the heart, are able to contract even when energy levels
are extremely low (they just might not be able to relax again).
After this systolic phase is the diastole, or “relaxation,” phase when
the ventricles fill up with blood. The diastole phase generally lasts less
than a third of a second but requires the most ATP. There are two
reasons, both of which were just discussed. First, energy is required
to separate the bonds formed during the contraction phase, which
allows the muscle to return to its relaxed state. Second, the removal of
calcium ions from the cell requires energy.
Without enough ATP, the calcium ions cannot be pumped out of
the heart muscle cells, and the heart can no longer relax and fill up
with blood efficiently. This is called diastolic dysfunction. The begin-
ning stages of diastolic dysfunction are characterized by a thickening
(called hypertrophy, or enlarging of the heart muscle, usually specific
to the left ventricle) and stiffening of the ventricular walls. The
combination of hypertrophy and stiffening causes blood pressure to
rise, reduces the amount of blood that’s pumped out per contraction
(lower ejection fraction), and makes it more difficult for the heart to
relax and fill up properly (which propagates this progressive cycle).
Despite seemingly normal systolic function, diastolic dysfunction
is an early sign of serious heart problems around the corner—namely,
congestive heart failure. Preserving diastolic function in patients is a
major goal for cardiologists, and the solution is to ensure an abundant
pool of ATP energy.
Another energy-intensive process in a heartbeat is maintaining a
proper ionic balance. The proper flow of ions in and out of a heart
muscle cell is essential to maintain the normal electrochemical
 The Dark Side of the Force   |  75

gradient across the cell membrane. This gradient is what’s respon-

sible for maintaining regular heart rhythm. When this gradient is
disrupted, the result is irregular or “skipped” heartbeats (arrhythmia)
or another type of abnormal contraction or rhythm.
All of these high energy demands must be met by a small pool of
ATP. As a result, the ATP supply must be continuously replenished—
and again, that is the job of our mitochondria. I’m hoping that by now
you can appreciate the important role mitochondria have in one of
the leading causes of death; but you’ll soon see that their importance
goes far beyond the cardiovascular system, and plays a crucial role in
essentially every functional system in the body.

The Role of Mitochondria in the

Nervous System, Brain, and Cognitive Health
Tissues with a high demand for energy are uniquely dependent on
the energy delivered by mitochondria and, therefore, also have the
lowest threshold for displaying symptoms of mitochondrial dysfunc-
tion. Thus, the central nervous system is often one of the first systems
to display outright symptoms of bioenergetic deficiencies. Large
amounts of energy are required by neurons (nerve cells) to carry out
their specialized functions.
In fact, while the brain makes up only about 2 percent of a person’s
body weight (which of course varies depending on the person), at
rest, it consumes about 20 percent of the total energy the body needs.
The brain is a giant tangle of countless neurons, so it would stand to
reason that this organ might suffer significantly from mitochondrial
dysfunction, and possibly respond best to mitochondrial nutrients.

Stroke: Suffocating the Brain’s Mitochondria

The cycling of blood through the circulatory system delivers a
constant supply of oxygen, glucose, and nutrients to every living cell.
The brain consumes a disproportionate share of the body’s circulat-
ing blood flow (14 percent) and oxygen (20 percent), yet despite its
extraordinary energy demand, the brain’s energy reserves are actually
very small. The brain’s metabolism can sustain energy production for