What are mitochondria?
Mitochondria are double-membrane organelles that populate by the hundreds or thousands the cytoplasm of all cells in the human body. Their main function is to produce energy through a metabolic process called oxidative phosphorylation (OXPHOS). More than ninety percent of the energy utilized by our organism is produced in the mitochondria. When a failure in energy supply occurs, due to defective mitochondrial OXPHOS, the life of the cell, and indeed that of our entire organism, is seriously at risk. Tissues and organs with the highest energy demand, including the brain, skeletal muscles, and the heart, are usually the most affected ones.

The OXPHOS process takes place in the internal membrane of mitochondria, through a sequential series of reactions of reduction and oxidation, which form the so called "cellular respiration" and are carried out by the four enzymatic complexes of the mitochondrial respiratory chain (Complex I, Complex II, Complex III, Complex IV or cytochrome-c-oxidase). In this reaction, electrons liberated by the controlled degradation of nutrients are ultimately combined with molecular oxygen to produce water. The energy liberated during these reactions is utilized by Complex V, or ATP-synthetase, to produce the compound adenosintriphosphate (ATP), the fundamental "fuel" for cellular metabolism. From a genetic point of view the respiratory chain has unique features since it is composed of proteins encoded by two different genetic systems: the nuclear genome, which is inherited from both parents, and the mitochondrial genome, which is inherited exclusively from the mother. As a consequence of this dual genetic inheritance, OXPHOS defects can be caused by mutations in either mitochondrial or nuclear genes.

The Mitochondrial Genome
Mitochondria have their own DNA (mtDNA). MtDNA is an extremely small, circular minichromosome, present in several copies in each organelle, and containing only thirty-seven genes. Thirteen genes encode as many protein subunits of the OXPHOS complexes, whilst twenty-four genes encode RNA molecules (2 ribosomal RNA, rRNA, and 22 transfer RNAs, tRNA) that are indispensable for the in situ synthesis of the mtDNA-encoded protein subunits.

During fertilization, mitochondria present in the new individual (zygote) are derived only from the egg cell. In principle, a mother carrying a mtDNA mutation will transmit it to all of her children, but only her daughters will be able to transmit this mutation on to the subsequent generation. This pattern of transmission is called maternal inheritance.

In contrast to the double nuclear gene copies, that are called paternal and maternal alleles, present in human nuclei, there are hundreds of mtDNA molecules contained in each cell. In a normal individual, all the mtDNA molecules are identical, a condition called homoplasmy. Deleterious mtDNA mutations generally strike only a fraction of the mitochondrial genomes of an individual, leading to the coexistence in cells and tissues of two mtDNA populations, one normal and one mutated. This condition is called heteroplasmy. However, it is only when the mutated genomes reach a critical threshold over the normal genomes, that an effective reduction of OXPHOS activity occurs and thus the clinical manifestations of disease.

Oxidative Phosphorylation: in mitochondria, oxygen inhaled during breathing burns sugars and fat contained in nutrients, producing carbon dioxide and energy,stored as ATP.

Map of human mitochondrial DNA.

Threshold effect in a cell line.