Enlightening Precision Medicine: Identification of mitochondrial DNA mutations on stroke patients

Identification: Carvalho, Filipa



Enlightening Precision Medicine: Identification of mitochondrial DNA mutations on stroke patients
Filipa S. Carvalho1, Ana C. Fonseca2, José M. Ferro2, Sofia Galego3, Vanessa A. Morais1
1iMM Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; 2Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Instituto de Medicina Molecular, Lisboa, Portugal; 3Unidade Cérebro Vascular do Hospital de São José, Lisboa, Portugal
Mitochondria are known as the “power house” of the cell by producing cellular energy through generation of ATP. Additionally, mitochondria are the only organelle, besides the nuclease, to have their own genome. Human mitochondrial DNA (mtDNA) is a 16.6 kb circular double-stranded DNA molecule that encodes for 37 genes. Mutations in these genes can cause impairment of the electron transport chain, rise of electron leakage and progressively increased ROS production, which can induce mitochondrial dysfunction and act as a primary indicator to an emergent disorder. Mitochondrial function in ischemia stroke is altered as a direct consequence of the impaired delivery of glucose and oxygen to the tissue and is further modified by changes in mitochondrial properties that develop during ischemia or following reperfusion. Limitations in the ability of cells to generate ATP can exacerbate the cellular response to other insults and can influence the cell death pathways developed after stroke insults. An accurate profiling of mitochondrial genome, as well as the pattern of changes in cellular energy metabolism, is essential to fully elucidate the mechanisms leading to tissue damage in ischemia. In order to progress towards the new era of Precision Medicine, we aim to define the genetic and bioenergetics profile of mitochondria present in afflicted individuals. For this, we will isolate mtDNA from blood stroke patients, and use next-generation sequencing methodologies to study the whole mitochondrial genome with the final aim of identifying mtDNA mutations that correlate with stroke incidence. For the bioenergetics profile, we will use cell-based assays that determine the ATP content, oxygen consumption rates and mitochondrial membrane potential levels. Ultimately, a computational pipeline for the integration of clinical, genetic and bioenergetics profile data will be developed. This platform will aid in generating a Precision Medicine strategy to correct mitochondrial dysfunction and predict stroke incidence.



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