Mitochondria, Health & Longevity

Group leader: Ian James Holt, Ph.D.

IIS Biodonostia. Ikerbasque Research Professor.
Dr. Ian Holt graduated from Newcastle University (Newcastle-upon-Tyne, UK) in 1985 and obtained his PhD at the London Institute of Neurology, University College London in 1989. Author of the discovery of the first genetic cause of mitochondrial diseases (deletions in mitochondrial DNA). Leader of the mitochondrial DNA replication programme at the British Medical Research Council for 17 years, he was a visiting researcher (in the Netherlands, Finland, the USA, etc.), places with which he currently maintains a series of collaborations. Having been named Honorary Professor by the London Institute of Neurology, University College of London in 2017, that same year he joined the Biodonostia HRI as an Ikerbasque Research Professor, Leader of the Mitochondria, Health and Longevity Group and member of the CIBERned (Network Centre for Biomedical Research in Neurodegenerative Diseases). The development of his research at the Institute is funded by the Carlos III Health Institute and the Basque Government Ministries of Health and Economy and Competitiveness. He is currently directing 3 doctoral theses, having supervised another 19, as well as a master’s degree student. He has published more than 100 articles in journals, particularly including Cell, Nature, EMBO, Nature Genetics and PNAS, accumulating more than 13,000 citations (Google Scholar) with an h-index of 56.

Strategic Objectives

Mitochondria produce energy from food, and essential to this process are their small circles of Mitochondrial DNA (mtDNA). mtDNA abnormalities have been widely implicated in neurodegeneration and the normal ageing process.

Dr. Ian James Holt is a world leader in the field of energy production and human disease with a special focus on the DNA in mitochondria. He identified the first disease causing mutations in human mtDNA 30 years ago and since then has made many important contributions to our understanding of mtDNA metabolism in normal and disease states.

The overarching aim of the Research Group is to understand the contribution of altered energy metabolism to neurodegeneration and ageing. The allied goal is to use this knowledge to design interventions to slow or prevent the progressive defects in energy metabolism in these contexts, and thereby extend human health-and life-span. A central component of the Group´s approach will be to dissect the processes of mtDNA metabolism and to understand how they impact the body in disease states and as we age.

Main lines of research

  • To determine the range of mtDNA abnormalities that afflicts humans with the emphasis on neurodegenerative disorders and ageing.
  • To determine the factors that underlie the progressive nature of mtDNA abnormalities especially the role of nutrient availability and utilization.
  • To utilize the information obtained in the previous point to design and develop interventions that slow, halt or reverse the accumulation of mutant mtDNA molecules.
  • To elucidate the contribution of interactions between the mitochondria and the endoplasmic reticulum to energy metabolism and mtDNA maintenance and its relevance to disease and ageing.
  • To dissect the cholesterol-mtDNA axis and its contribution to neurodegenerative disease and ageing.
  • The molecular basis of SPG7 deficiency; shining light on the boundary of motor neuron and mitochondrial disease.
  • Experimental modelling of ALS.
  • The development and testing of small molecules to combat pathological mtDNAs.

Team Members

Scientific Output