1 Introduction

Mitochondria are the powerhouses of our cells. They are responsible for generating energy as adenosine triphosphate (ATP) and heat, and are involved in the apoptosis-signaling pathway. Current theory holds that mitochondria are the descendants of aerobic bacteria that colonized an ancient prokaryote between 1 and 3 billion years ago [1–3]. This allowed for the evolution of the first eukaryotic cell capable of aerobic respiration, a necessary precursor to the evolution of multicellular organisms [1]. Supporting this theory is the observation that mitochondria are the only other subcellular structure aside from the nucleus to contain DNA.  However, unlike nuclear DNA (nDNA), mitochondrial

DNA (mtDNA) are not protected by histones [4]. nDNA wraps around histones, which then physically shield the DNA from damaging free radicals [5] and are also required to repair dsDNA breaks [6]. Since mtDNA lacks the structural protection of histones and their repair mechanisms, they are quite susceptible to damage.

The first mitochondrial disease was described by Luft and et al. in 1962 [7], when a euthyroid 35-year-old female presented with myopathy, excessive perspiration, heat intolerance, polydipsia with polyuria, and a basal metabolic rate 180% of normal. The patient suffered from an uncoupling of oxidative phosphorylation (ox-phos). Ox-phos is the major cellular energy-producing pathway. Energy, in the form of ATP, is produced in the mitochondria through a series of reactions in which electrons liberated from the reducing

substrates nicotine adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH) are delivered to O2 via a chain of respiratory proton (H+) pumps [8]. The uncoupling

of ox-phos leads to the generation of heat without generating ATP, which was the dysfunction underlying this

Table 1. Signs, symptoms and diseases associated with mitochondrial dysfunction [29]

Organ system                      Possible symptom or disease

Muscles                                Hypotonia, weakness, cramping, muscle pain, ptosis, opthalmoplegia

Brain                                      Developmental delay, mental retardation, autism, dementia, seizures, neuropsychiatric disturbances,  atypical cerebral palsy, atypical migraines, stroke, and stroke-like events

Nerves                                   Neuropathic pain and weakness (which may be intermittent), acute and chronic inflammatory demyelinating     polyneuropathy, absent deep tendon reflexes, neuropathic gastrointestinal problems (gastroesophageal          reflux, constipation, bowel pseudo-obstruction), fainting, absent or excessive sweating, aberrant temperature           regulation

Kidneys                                 Proximal renal tubular dysfunction (Fanconi syndrome); possible loss of protein (amino acids), magnesium,         phosphorus, calcium, and other electrolytes

Heart                                     Cardiac conduction defects (heart blocks), cardiomyopathy

Liver                                       Hypoglycemia, gluconeogenic defects, nonalcoholic liver failure

Eyes                                       Optic neuropathy and retinitis pigmentosa

Ears                                        Sensorineural hearing loss, aminoglycoside sensitivity

Pancreas                               Diabetes and exocrine pancreatic failure

Systemic                               Failure to gain weight, short stature, fatigue, respiratory problems including intermittent air hunger.

Table 2. Acquired conditions in which mitochondrial dysfunction has been implicated

Diabetes [3, 10, 11] Huntington's disease [12] Cancer [3], including hepatitis-C virus-associated hepatocarcinogenesis [13] Alzheimer disease [12] Parkinson's disease [12] Bipolar disorder [14, 15]

Schizophrenia [15] Aging and senescence [3, 16–19] Anxiety disorders [20] Nonalcoholic steatohepatitis [21]  Cardiovascular disease [10], including atherosclerosis [22] Sarcopenia [23] Exercise intolerance [24]

Fatigue, including chronic fatigue syndrome [25, 26], fibromyalgia [27, 28], and myofascial pain [28]

patient's presentation. To compensate, her mitochondria enlarged and multiplied, which was evident in a histological examination of muscle biopsies. 

Since this first documented case, mitochondrial dysfunction has been implicated in nearly all pathologic and toxicologic conditions [9] (these conditions are outlined in Tables 1–3). The conditions include sarcopenia and nonalcoholic steatohepatitis; acquired diseases such as diabetes and atherosclerosis; neurodegenerative diseases such as Parkinson's and Alzheimer's diseases; and inherited diseases, collectively called mitochondrial cytopathies.  However, since symptoms vary from case to case, age of onset, and rate of progression, mitochondrial dysfunction can be difficult to diagnose when it first appears. According to BH Cohen, who wrote a July 2001 article in the Cleveland Clinic Journal of Medicine, “The early phase can be mild and may not resemble any known mitochondrial disease.  In addition, symptoms such as fatigue, muscle pain, shortness of breath, and abdominal pain can easily be mistaken for collagen vascular disease, chronic fatigue syndrome, b fibromyalgia, or psychosomatic illness” [29].

2 Mitochondria structure and function

Cellular energy requirements control how many mitochondria are in each cell. A single somatic cell can contain from 200 to 2000 mitochondria [30, 31], while human germ cells such as spermatozoa contain a fixed number of 16 mitochondria and oocytes have up to 100000 [32]. The largest number of mitochondria are found in the most metabolically active cells, such as skeletal and cardiac muscle and the liver and brain. Mitochondria are found in every human cell except mature erythrocytes [29]. 

Mitochondria produce more than 90% of our cellular energy by ox-phos [33]. Energy production is the result of two closely coordinated metabolic processes – the tricarboxylic acid (TCA) cycle, also known as the Krebs or citric acid cycle, and the electron transport chain (ETC). The TCA cycle converts carbohydrates and fats into some ATP, but its major job is the capture of electrons by the coenzymes NADH and FADH which shuttle this energy to the ETC.  The overall pathway for the TCA cycle is as follows: catabolism of glucose in the cytosol  produces two molecules of pyruvate, which pass through the mitochondrion's double membrane to enter the TCA cycle. As the pyruvate molecules pass through the membranes, they encounter two enzymes, pyruvate carboxylase and pyruvate dehydrogenase (PDH). Although PDH is referred to as one enzyme, it

is actually a complex of three separate enzymes – PDH, dihydrolipoyl transacetylase, and dihydrolipoyl dehydrogenase.  The PDH complex requires a variety of coenzymes and substrates for its function – coenzyme A (CoA), which is derived from pantothenic acid (vitamin B5); NAD+, which contains niacin (vitamin B3); FAD+, which contains riboflavin (vitamin B2); lipoic acid; and thiamin pyrophosphate (TPP), which, as the name indicates, contains thiamin (vitamin B1).

When there is ample energy (relatively high concentrations of ATP), pyruvate carboxylase is activated and shut-

Table 3. Inherited conditions in which mitochondrial dysfunction has been implicated [29]

Syndrome                                                           Symptoms

Kearns–Sayre syndrome (KSS)      external ophthalmoplegia, cardiac conduction defects, and sensorineural hearing

Leber hereditary optic neuropathy(LHON) visual loss in young adulthood

Mitochondrial encephalomyopathy,      varying degrees of cognitive impairment and dementia, lactic,                                                                                       i                                                          acidosis stroke

and stroke-like syndrome (MELAS)      and transient ischemic attacks 

Myoclonic epilepsy and ragged-red fibers (MERRF) progressive myoclonic epilepsy, clumps of diseased                 m                                               mitochondria accumulate in the subsarcolemmal region of the muscle fiber

Leigh syndrome subacute sclerosing encephalopathy    seizures, altered states of consciousness, d                       de                                                                                     dementia, ventilatory failure

Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)    dementia, in addition to the symptoms d                         e                                                                                                   described in the acronym

Myoneurogenic gastrointestinal encephalopathy

(MNGIE)          

                                                                   gastroinstestinal pseud-obstruction, neuropathy