Do longitudinal changes in the mitochondrial transcriptome modulate age-related disease risk?

Lead Supervisor
Dr Alan Hodgkinson
MRC eMedLab Fellow
Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King’s College London
alan.hodgkinson@kcl.ac.uk 

Co-supervisor
Dr Kerrin Small
Department of Twin Research & Genetic Epidemiology, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King’s College London

Project Details

Mitochondria are involved in a wide range of fundamental cellular processes, from cellular energy production to thermogenesis, lipid biosynthesis and cell death. So wide ranging are their functions, that diseases associated with mitochondria manifest across almost all tissues, often affecting multiple organs simultaneously. Mitochondria have their own genome that codes for a small number of proteins that form core components of the electron transport chain, thus modulating key metabolic processes. However, proteins encoded in the nuclear genome control many of the processes occurring in mitochondria, thus making interactions between the nuclear and mitochondrial genomes key to health. 

A decline in mitochondrial quality is a general hallmark of ageing, and most aging-related diseases (particularly those originating in high energy tissues such and the heart and brain) have mitochondrial involvement. Despite this, little is known about the trajectory of mitochondrial genetics and transcription through time as individuals age, and whether this correlates with disease incidence. To interrogate this issue, this project will utilise rich genetic and phenotype information from the TwinsUK cohort, where longitudinal health and gene expression data has been collected at three different time points over a period of nine years for ~350 individuals.

Within this, the project will aim to answer three key questions:

  1. Does genetic damage to the mitochondrial genome occur at different rates across the population, and does this correlate with the decline of health?
  2. Are there differences in the way that the mitochondrial transcriptome is processed over time (e.g. RNA modification and gene expression levels) and is this related to metabolic disorders?
  3. Are there feature of the mitochondrial genome and accompanying relationships with the nuclear genome that are predictive of disease risk?

Datasets

Data from TwinsUK – consent and ethics has been obtained within the project for research purposes.

Keywords

Transcriptome, RNA sequencing, age-related disease, mitochondria, metabolic disease