Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups
Open Access
- 21 June 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 19 (17), 3343-3353
- https://doi.org/10.1093/hmg/ddq246
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.Keywords
This publication has 56 references indexed in Scilit:
- Mitochondrial DNA variability modulates mRNA and intra-mitochondrial protein levels of HSP60 and HSP75: experimental evidence from cybrid linesCell Stress and Chaperones, 2009
- “ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis”—a critical commentaryFree Radical Biology & Medicine, 2008
- Regulatory interactions in the dimeric cytochrome bc1 complex: The advantages of being a twinBiochimica et Biophysica Acta (BBA) - Bioenergetics, 2008
- Cosegregation of novel mitochondrial 16S rRNA gene mutations with the age-associated T414G variant in human cybridsNucleic Acids Research, 2008
- Experimental assessment of bioenergetic differences caused by the common European mitochondrial DNA haplogroups H and TGene, 2008
- Simultaneous detection of apoptosis and mitochondrial superoxide production in live cells by flow cytometry and confocal microscopyNature Protocols, 2007
- Direct linkage of mitochondrial genome variation to risk factors for type 2 diabetes in conplastic strainsGenome Research, 2007
- Antioxidants tiron and N-acetyl-L-cysteine differentially mediate apoptosis in melanoma cells via a reactive oxygen species-independent NF-κB pathwayFree Radical Biology & Medicine, 2007
- An enhanced MITOMAP with a global mtDNA mutational phylogenyNucleic Acids Research, 2006
- Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in miceNature Genetics, 2003