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Mitochondria Versus Nucleus

Disruptions in the interaction between nuclear and mitochondrial DNA can lead to deficiencies in the mitochondrial energy-generating process, affecting fitness.

By | February 15, 2013

Graphical illustration of a mitochondrionFLICKR, BIOLOGY FLASHCARDSInteractions between the nuclear genome and mitochondrial DNA are essential for proper cellular functioning, but incompatibilities between the two can lead to compromised development and fitness according to research published last month (January 31) in PLOS Genetics.

“The work is most important for its fine dissection of a mito-nuclear interaction and its consequences for phenotypic variation and fitness,” said marine biologist Ron Burton, who wasn’t involved in the study. “These results show that we can't expect to understand mitochondrial diseases by associations with mitochondrial DNA variation alone.”

Despite having their own genomes, mitochondria don’t make many of their own proteins; most are synthesized in the cytosol by cellular equipment encoded in the nucleus. Thus, the interactions of mitochondrial and nuclear DNA are critical to cellular life. But there is some evidence that mutations can disrupt the smooth-running of the interactions, resulting in incompatibilities between the two genomes.

In the new study, Colin Meiklejohn and colleagues worked with Drosophila melanogaster hybrids.  Each hybrid combined one of two different nuclear genomes with one of three types of mitochondrial DNA, making six strains altogether. Five of these six were healthy, but the strain with D. melanogaster OregonR nuclear genes and D. simulans simw501 mitochondrial DNA showed developmental, physiological, and reproductive problems. The researchers had discovered a mitochondrial-nuclear incompatibility, albeit a man-made one.

“The incompatibility is ’artificial’ in the sense that the mitochondrial and nuclear genomes were matched from two sister species of fruit fly - in natural populations they would never naturally occur together,” evolutionary biologist Damian Dowling of Monash University, who didn’t participate in the work, told The Scientist in an email. “It is likely that these incompatibilities do, however, exist in nature, within the same species/populations, and we have some preliminary evidence for such incompatibilities.”

Finding the incompatibility was just the start, though. The researchers were able to use the mitochondrial-disease model they had developed to look for the underlying mechanisms.

Through genetic mapping, Meiklejohn and his colleagues localized the nuclear factor responsible for the incompatibility on chromosome two. Then, by concentrating just on the development delays in the fruit flies, they were able to further narrow the field to a region containing just nine genes: these genes, when combined with the D. simulans mitochondrial DNA, were entirely responsible for the delayed development.

Scouring these nine genes for differences from the compatible genomes, the researchers identified a single gene, which encodes a tyrosine tRNA synthetase, carrying a point mutation that caused a valine to be coded where an alanine should have been. The team also traced the mitochondrial mutation to a single nucleotide polymorphism in the tyrosine tRNA gene.

Neither mutation by itself affected fitness—those fly strains that carried either one were healthy. But having both mutations meant that the synthestase couldn't properly attach tyrosine to the tRNA, and this resulted in disrupted translation.

Biochemical investigations backed up the genetic findings. Analyzing mitochondrial enzymes, the team discovered reduced activity in three OXPHOS complexes, proteins involved in the mitochondrial energy-generating process. And since around 90 percent of a cell’s ATP typically derives from the OXPHOS metabolic pathway, the reduced function means less energy is available for cell growth and development.

“Reduced activity of all three OXPHOS complexes suggests compromised transcription or translation of mitochondrial DNA,” Burton said. “Reduced activities probably impact fitness in several ways.”

The results point to the importance of the mitochondria-nucleus interactions and may inform our understanding of human mitochondrial disorders, about half of which are caused by mitochondrial mutations in tRNA genes. Despite having identified many of these mutations, scientists have found little correlation with disease: different mutations can lead to similar symptoms, while the same mutations can promote very different diseases. And even more puzzling, not everyone with a pathological tRNA mutation becomes ill; some individuals remain healthy. The new research suggests that these inconsistent findings may stem from mitochondrial-nuclear interactions: the nuclear-encoded tRNA synthetase has to be compatible with its associated mitochondrial tRNA for fully functioning protein synthesis.

“If there is natural variation in human populations for the appropriate tRNA synthetase, the disease phenotype might only occur in specific mitonuclear genotypes,” said Burton. “The implications for human mitochondrial medicine are substantial.”

C.D. Meiklejohn et al., “An incompatibility between a mitochondrial tRNA and its nuclear-encoded tRNA synthetase compromises development and fitness in Drosophila,” PLOS Genetics, 9(1): e1003238. doi:10.1371/journal.pgen.1003238, 2013.

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Avatar of: barrybarclay

barrybarclay

Posts: 10

February 19, 2013

This is a very interesting study that I think also has application to carcinogenesis. It could be argued that in many ways tumor formation is a breakdown in the contract between the nucleus and mitochondria just as described in the paper, a decrease in evolutionary fitness in microcosm and allowing for the emergence of a novel pathology.  The ancient endosymbiotic contract breaks down because of ongoing genomic damage to both organelles. The resultant stress response causes greatly increased rates of muation and mitotic recombination converting numerous proto-oncogenes to their oncogenic form and the expression of recessive tumorigenic alleles by loss of heterozygosity. Mitochondria with damaged genomes diminish fitness in cell lineages by decreasing the efficiency of apoptotic surveillance mediated by the TP53 family of genes and allowing for increased survival of damaged tumorigenic genomes in the nucleus. mt DNA damage would also cause respiratory deficiency shifting cell lineages from OXPHOS to glycolysis even in the presence of an adequate oxygen supply the "Warburg" effect.

Avatar of: James V. Kohl

James V. Kohl

Posts: 152

February 19, 2013

The induced valine alanine point mutation reduces fitness in Drosophila but  natural selection for the alanine substitution appears to increase fitness in humans.

Is thermoregulation of intranuclear RNA and protein biosynthesis in species from microbes to Drosophila and thermoregulation of human body temperature controlled by the molecular mechanisms common to all species? 

Are the epigenetic effects of nutrient stress and social stress on thermoregulation of intranuclear RNA and protein biosynthesis causing the blebs I just read about?

Avatar of: Alexandru

Alexandru

Posts: 61

February 20, 2013

Please, just read my research exposed in " Mitochondrial Adam DNA data transmissions theory" - ISBN 978-606-92107-1-0

Abstract: Brain and soul storming - The necessary and sufficient processes to a well function of the human body are meticulous arranged by specific organizational cells, so called process bio-managers, using interconditioned procedures, transmitted through three ways of communication: chemical or “protein channel”, electrical or “ion channel” and mitochondrial or “EMF wireless channel”. The third type is out of the visible and measurable spectrum and raises a new challenge to the scientist. For this type of bio communication we bring a new theoretical hypothesis, based on the managerial multidisciplinary analysis of a cybernetic model proposed by us, by simulating the human body function with the virtual computerized system based on the management of its total knowledge and its perfect quality way of function. The main bricks used for this virtual construction are: the brain, as main bio-processor, and Eve mtDNA and Adam mtDNA, as bio-antennas. This assembly of the total knowledge, build with “brain reasoning, biological feeling, and unlimited soul feeling”, is called by us “main decision triangle, IQ-EQ-CQ”. The main principle of the management of the total knowledge imposes us to not neglect the information produced by man during the time, even if it seems creasy at the beginning (see brainstorming definition). Because in the natural fertilisation the spermatozoids are naturally equipped with the paternal mtDNA (it looks like reflex klystron power amplifier, KPA = a veritable main bio-GPS), we consider that the paternal mitochondria DNA have a very important role in the evolution of the human being life quality and we have developed a new hypothesis, “Adam mtDNA theory”, in addition to “Eve mtDNA theory”.

Keywords: brain, mitochondria, maternal, paternal

 

 

 

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