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Mitochondrial DNA variants in late-onset human diseases

Pioneering discovery of a new genetic checkpoint and biomarker to track human diseases.

Mitochondria are the energy factories of the body and as such key organelles in each cell. Importantly, mitochondria harbor their own DNA (mitochondrial DNA, mtDNA) that encodes the proteins of the electron transport chain plus the RNA machinery necessary for their transcription and translation. Because of the ubiquitous and essential roles of these mtDNA-encoded proteins in cellular metabolism, it is not surprising that mtDNA variants influence the risk of acquiring late-onset human diseases, including neurodegenerative diseases such as Alzheimer’s or Parkinson’s, cardiovascular malignancies or metabolic disorders including type 2 diabetes.
“Although all these represent widespread diseases and the relevance of mtDNA variations to them is apparent, we are lacking a clear understanding of the molecular underpinnings of genetic associations on the mtDNA, especially if out of the direct mitochondrial context”, states Dr. Na Cai, Head of the Translational Genetics Group at HPC and first author of the study summarized below.
To assess how mtDNA variants influence physiology and complex diseases, Na and her colleagues performed the first large-scale functional assessment of effects of common mtDNA variations using high-throughput metabolomics, transcriptomics, and proteomics approaches. The team took a phenomenon-driven, unbiased approach to assess the impact of mtDNA polymorphisms on a wide set of ~ 6000 molecular and metabolic traits excluding ATP synthesis. Their study, recently published in Nature Medicine, demonstrates how mtDNA-mediated regulation of N-formylmethionine (fMet) influences cellular protein homeostasis, providing a so far unknown genetic checkpoint and an easy to measure circulating blood biomarker for late-onset diseases.


“Only the joint efforts of many brilliant scientists brought this study to life and I am excited to continue these fruitful collaborations in the future”,
Na concludes.



Very interestingly, higher fMet levels also increased the ubiquitin-dependent proteolysis with a concomitant decrease in protein aggregation and up-regulation of apoptosis, providing a potential explanation for previously found protective effects of fMet on late-onset neurodegenerative disorders.
Therefore, the authors emphasize the importance of maintaining cellular fMet levels within a narrow physiological range, a result that will raise significant interests assessing both effects and predictive value of fMet fluctuations for various human diseases. Based on the new insights, fMet presents a highly promising blood biomarker for monitoring established and novel treatments across a wide range of common human malignancies.
The successful team consisted of scientists from the Wellcome Sanger Institute (UK), EMBL-EBI (UK), University of Cambridge (UK), John Radcliffe Hospital (UK), Newcastle University (UK), British Heart Foundation Centre of Research Excellence, University of Cambridge and the EMBL Heidelberg (Germany).

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