Inherited mitochondrial DNA variants can affect complement, inflammation and apoptosis pathways: insights into mitochondrial-nuclear interactions

Abstract

Age-related macular degeneration (AMD) is the leading cause of vision loss in developed countries. While linked to genetic polymorphisms in the complement pathway, there are many individuals with high risk alleles that do not develop AMD, suggesting that other 'modifiers' may be involved. Mitochondrial (mt) haplogroups, defined by accumulations of specific mtDNA single nucleotide polymorphisms (SNPs) which represent population origins, may be one such modifier. J haplogroup has been associated with high risk for AMD while the H haplogroup is protective. It has been difficult to assign biological consequences for haplogroups so we created human ARPE-19 cybrids (cytoplasmic hybrids), which have identical nuclei but mitochondria of either J or H haplogroups, to investigate their effects upon bioenergetics and molecular pathways. J cybrids have altered bioenergetic profiles compared with H cybrids. Q-PCR analyses show significantly lower expression levels for seven respiratory complex genes encoded by mtDNA. J and H cybrids have significantly altered expression of eight nuclear genes of the alternative complement, inflammation and apoptosis pathways. Sequencing of the entire mtDNA was carried out for all the cybrids to identify haplogroup and non-haplogroup defining SNPs. mtDNA can mediate cellular bioenergetics and expression levels of nuclear genes related to complement, inflammation and apoptosis. Sequencing data suggest that observed effects are not due to rare mtDNA variants but rather the combination of SNPs representing the J versus H haplogroups. These findings represent a paradigm shift in our concepts of mt-nuclear interactions.

Mitochondrial DNA haplogroups influence the risk of incident knee osteoarthritis in OAI and CHECK cohorts. A meta-analysis and functional study

“…Because of that, these cell models have been proposed and widely used to explore the contribution of mitochondrial dysfunction and mtDNA mutations to the pathogenesis of human diseases, such as Parkinson or cancer 45 46. Through the use of this cellular model, recent studies showed that J variant associates with decreased expression of specific genes related to inflammatory response, complement and apoptosis when compared with the haplogroup H 12. The functional analysis described herein included specific metabolic measurements using an extracellular flux analyser as well as specific aspects proposed to be related to OA, such as mitochondrial reactive oxygen species (ROS) production, oxidative stress and apoptosis 7 44 47.…”

“…Each of the mtDNA haplogroups harbours specific single nucleotide polymorphisms (SNPs) that influence the behaviour of the mitochondria11 and interact with the nuclear genome,12 influencing our health today 10. Some of these genetic variants have been associated with degenerative disorders,13 metabolic alterations14 or even increased longevity in humans 15…”

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

“…The concept that mtDNA can direct the mode of energy production of the cell was supported by recent cybrid studies conducted by Dr. C. Kenney’s group [75, 76]. Cybrids are created by removing mitochondria from a cell line by passaging in presence of ethidium bromide.…”

Mitochondrial DNA SNPs associated with Schizophrenia exhibit Highly Variable Inter-allelic Haplogroup Affiliation and Nuclear Genogeographic Affinity: Bi-Genomic Linkage Disequilibrium raises Major Concerns for Link to Disease

“…12, 2017; epidemiological characteristics of SZ obviously increase the risk of spurious associations caused by subtle admixture and 2GLD. However, it does not per se refute the mitochondrial pathogenic paradigm 34 where variation in mitochondrial function, believed to interfere with ATP production 35,36 , inflammation and signaling 37,38 as well as Ca 2+ -homeostasis 39 , and apoptosis 38 , is considered to be of paramount importance for development of disease. Several neuroanatomical postmortem findings in SZ brains indicate perturbed mitochondrial function 40 , but such findings are difficult to distinguish from changes caused by drug treatment.…”