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Many epidemiologic studies have associated human mitochondrial haplogroups to rare mitochondrial diseases like Leber's hereditary optic neuropathy or to more common age-linked disorders such as Parkinson's disease. However, cellular, biochemical and molecular-genetic evidence that is able to explain these associations is very scarce. The etiology of multifactorial diseases is very difficult to sort out because such diseases are due to a combination of genetic and environmental factors that individually only contribute in small part to the development of the illness. Thus, the haplogroup-defining mutations might behave as susceptibility factors, but they could have only a small effect on oxidative phosphorylation (OXPHOS) function. Moreover, these effects would be highly dependent on the 'context' in which the genetic variant is acting. To homogenize this 'context' for mitochondrial DNA (mtDNA) mutations, a cellular approach is available that involves the use of what is known as 'cybrids'. By using this model, we demonstrate that mtDNA and mtRNA levels, mitochondrial protein synthesis, cytochrome oxidase activity and amount, normalized oxygen consumption, mitochondrial inner membrane potential and growth capacity are different in cybrids from the haplogroup H when compared with those of the haplogroup Uk. Thus, these inherited basal differences in OXPHOS capacity can help to explain why some individuals more quickly reach the bioenergetic threshold below which tissue symptoms appear and progress toward multifactorial disorders. Hence, some population genetic variants in mtDNA contribute to the genetic component of complex disorders. The existence of mtDNA-based OXPHOS differences opens possibilities for the existence of a new field, mitochondrial pharmacogenomics. New sequence accession nos: HM103354-HM103363.

Despite the strong purifying selection that occurs during embryonic development, the particular location and features of mitochondrial DNA make it especially susceptible to accumulating point mutations, giving rise to a large number of mitochondrial DNA variants. Many of these will have moderate or no phenotypic effects but others will be the cause of very dramatic diseases, usually known as mitochondriopathies. Because of the abundance of different mitochondrial DNA variants, it is not easy to determine whether a new mutation is pathogenic. To facilitate this task, different criteria have been proposed, but they are often either too severely or too loosely applied. Citing examples from the literature, in this paper we discuss some critical aspects of these criteria.

Mitochondrial diseases, or diseases of the oxidative phosphorylation system, consist of a group of disorders originated by a deficient synthesis of ATP. This system is composed of proteins codified in the two genetic systems of the cell, the nuclear and the mitochondrial genomes, and, therefore, the mode of inheritance could be either mendelian or maternal. The diseases can also appear sporadically. Due to the central role that mitochondria play in cellular physiology, these diseases are a social and health problem of great importance. They are considered rare diseases; however, together they constitute a large variety of genetic disorders. It is also believed that mitochondria are involved, directly or indirectly, in many other human diseases, mainly in age-related diseases. This review will focus mainly on describing the special characteristics of the mitochondrial genetic system and the diseases caused by mitochondrial DNA mutations. We will also note the difficulties in studying these pathologies, and the possible involvement of the genetic variability of the mitochondrial genome in the development of these diseases.

The transcription of mitochondrial DNA has been studied for 30 years. However, many of the earlier observations are still unsolved. In this review we will recall the basis of mitochondrial DNA transcription, established more than twenty years ago, will include some of the recent progress in the understanding of this process and will suggest hypotheses for some of the unexplained topics. Moreover, we will show some examples of mitochondrial pathology due to altered transcription and RNA metabolism.