Normal Mitochondrial Function

Mitochondria are organelles responsible for energy production for the cell and also regulate apoptosis. Substances such as fatty acids and glucose are converted to ATP by the process of oxidative phosphorylation (OXPHOS).[1, 2] The mitochondria contains an inner and outer membrane which allows for the formation of electrochemical gradients across the inner membrane to drive energy production.

When food is consumed, fats are broken down into acetyl CoA and carbohydrates are converted to pyruvate. The electrons from the calories consumed are gathered by the tricarboxylic acid (TCA) cycle and β- oxidation. These electrons are then transferred to either NAD- to form NADH or FAD to form FADH2.[1] NADH transfers the electrons to complex I in the electron transport chain (ETC), where the they are oxidized. From the TCA cycle, succinate transfers electrons to complex II. Both succinate and NADH transfer electrons to ubiquinone, or coenzyme Q10 or CoQ, to form ubiseminquinone (CoQH-) and ubiquinol (CoQH2). Electrons from ubiquinol are then transferred to complex III, cytochrome c, and then complex IV. Following this, the electrons are transferred to ½ O2 and water is formed. The ETC releases energy, which drives protons across the inner membrane to form an electrochemical gradient. This potential energy causes complex V to convert ADP+Pi to ATP[1], or a usable form of energy for the cell. The following chart depicts this process.

Figure 1. From fuel to energy

The last step of this process, conversion of ADP to ATP, is known as oxidative phosphorylation. ATP is then exchanged for ADP in the cytosol by adenine nucleotide translocator (ANT). [1]


Mitochondria produce heat by releasing protons from the inner membrane space to the mitochondrial matrix, a process known as uncoupling. [5] This decreases the proton gradient necessary for ATP synthesis. Coupling efficiency is the efficiency of the electrochemical gradient to produce ATP through oxidative phosphorylation. [1]

Reactive oxygen species

Mitochondria is the primary source of reactive oxygen species (ROS) in the body. [3, 4] The electron transport chain involves a series of oxidation-reduction reactions that transfer electrons through a cascade as simply depicted in figure 1. This electron transfer pumps protons into the inner membrane space, which creates the electrochemical gradient that drives ATP synthesis. However, electrons can escape this cascade, essentially leaking into the inner matrix of the mitochondria. The electrons bind with O2 to create superoxide anion (O2-·), one example of a reactive oxygen species. [1]

e- + O2 → O2-·

ROS production from electron leakage in the ETC primarily occur at complex I and III. [3]

ROS "buffering" by natural antioxidants

The body has a natural process to counteract the creation of free radicals. The first line of defense is the the reaction of superoxide with manganese superoxide dismutase (MnSOD) to create the generate the relatively stable hydrogen peroxide (H2O2) as demonstrated. [1]

O2-· + (MnSOD) → H2O2

To increase stability, hydrogen peroxide, in the presence of glutathione peroxidase (GPx), yields water. [1]

H2O2 + (GPx) → H2O

However, hydrogen peroxide can react with transition metals yielding a hyrdroxyl radical, the most dangerous ROS. [1]

H2O2 + (transition metals) → OH-·

Mitochondrial DNA


PPAR gamma coactivator 1α (PGC-1α) is the master regulator of mitochondrial biogenesis and gene experission. [4] It coactivates NRF-1 and PPAR-γ and PPAR-α. ([5)]
The expression of PGC-1α is increased with increased cellular stress. [5]

mtDNA and Reactive oxygen species

Mitochondrial DNA (mtDNA) are particularly susceptible to damage by ROS for two main reasons:
1. Lack of protective histones
2. Close proximity to the inner mitochondrial membrane, where electrons are leaked.

Mitochondrial damage can result in increased electron leakage, and therefore increased ROS. This creates a positive feedback loop in which mtDNA damage and ROS continue to increase.

Role of Calcium

Calcium is an important regulator of mitochondrial function and serves several purposes that are vital to the cell. The primary role of mitochondrial calcium is the stimulation of oxidative phosphorylation. [6] Elevated calcium allows for upregulation of the entire oxidative phosphorylation system, which results in faster respiratory chain activity and a greater production of ATP. With more mitochondrial ATP, the cellular demands of ATP can be met. [6] Mitochondrial ROS are not just by-products of respiration, but are important for cell signaling. Aerobic metabolism is a fine balancing act of maximizing ATP generation while maintaining just the right amount of ROS required for cell signaling. [6] A “two-hit hypothesis” postulates that a concurrent diseased stimulus can turn calcium from “physiologic” to “pathologic”. Calcium is “physiologic” in that it promotes ATP synthesis, but it can become “pathologic” when it is present with a pathological stimulus, which in turn increases ROS production and promotes cell death. [6]

1. Wallace DC. The mitochondrial genome in human adaptive radiation and disease: On the road to therapeutics and performance enhancement. Gene. 2005;354:169-180.
2. Chabi B, Adhihetty PJ, Ljubicic V, Hood DA. How is mitochondrial biogenesis affected in mitochondrial disease? Med Sci Sports Exerc. 2005; 37(12): 2102-2110.
3. Ren J, Pulakat L, Whaley-Connell A, Sowers JR. Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease. J Mol Med 2010; 88:993-1001.
4. Bugger H and Abel ED. Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome. Clinical science. 2008;114:195-210.
5. Kim JA, Wei Y, Sowers JR. Role of mitochondrial dysfunction in insulin resistance. Circulation research. 2008;102:401-414.
6. Brookes PS, Yoon Y, Robotham JL, Anders MW, and Sheu S. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol. 2004;287(4):C817-C833.
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