Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups

Abstract

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.

Molecular-genetic characterization and rescue of a TSFM mutation causing childhood-onset ataxia and nonobstructive cardiomyopathy

“…5 This mutation provokes an important decrease in the EFTs levels, but the EFTu amount is not affected (Figure 1d). A mitochondrial protein synthesis analysis 6 also showed an important decrease in the levels of mtDNAencoded polypeptides (Figure 1e). …”

Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease

“…mtDNA haplogroups have been shown to modulate the efficiency of adenosine triphosphate synthesis or the production of reactive oxygen species, 26 and these effects could directly modulate neuronal protection rather than damage. It also likely that haplogroups J, T, and K are genetic tags of further mtDNA variation not directly genotyped in this study.…”

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

“…Additional haplogroup association studies also conclude that particular mtDNA haplogroups or haplogroup clusters may influence PD risk although risk attributions between the different populations analyzed do vary (5,38,102,151). The question of whether mtDNA haplogroups are functionally relevant has also been raised, and one recent cybrid study did find differences in mitochondrial respiratory capacity in cells containing haplogroup H versus haplogroup Uk (40). Other cybrid studies have similarly reported that common mtDNA polymorphisms may influence mitochondrial function (54,99).…”

“…It increasingly appears these polymorphisms may subtly influence mitochondrial function (40,54,99). This may apply to even extremely common synonymous mtDNA polymorphisms that do not cause amino acid substitutions (70).…”